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Safety
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Most premature infants require mechanical ventilation for prolonged periods of time and a significant proportion of them develop Bronchopulmonary Dysplasia (BPD). Caffeine is a stimulant of the respiratory center and has been used for the treatment of Apnea of Prematurity in infants not requiring mechanical ventilation or to facilitate weaning from mechanical ventilation by starting therapy shortly before extubation. Recently the use of Caffeine in ventilated infants has been initiated earlier because of the reported reduction in BPD. However there is paucity of data supporting this practice.
Because protracted mechanical ventilation and supplemental oxygen increase the risk of developing BPD, a therapy that would facilitate the reduction of the respiratory support and shorten its duration is desirable. Therefore, it is of importance to evaluate the effects of early Caffeine initiation and administration during the course of mechanical ventilation in preterm infants by means of a randomized placebo-controlled trial.
Hypothesis:
The primary hypothesis of this study is that early use of caffeine in mechanically ventilated preterm infants will reduce the time to first elective extubation and secondarily, that this will reduce the total duration of mechanical ventilation and oxygen supplementation, and reduce the incidence and severity of BPD.
Objective:
The objective of this trial is to evaluate the effects of early caffeine use during mechanical ventilation on the time to first elective extubation, total duration of mechanical ventilation and oxygen supplementation, and the incidence of BPD.
Study Design:
This will be a single-center prospective, randomized, double-blind, placebo controlled clinical trial.
Population:
Premature neonates born between 23 and 30 completed weeks of gestation, who require mechanical ventilation within the first 5 days of life will be enrolled. Infants with major congenital anomalies or small for gestational age will be excluded.
Methods:
Infants will be randomized within the first 5 days to receive a study drug consisting of either blinded Caffeine citrate or blinded Placebo (equivalent volume of normal saline). Infants will continue to receive the study drug until the first elective extubation.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Caffeine Arm | Experimental | Subjects randomized to this arm will receive blinded Caffeine citrate. |
|
| Placebo Arm | Placebo Comparator | Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Caffeine citrate | Drug | Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| Measure | Description | Time Frame |
|---|---|---|
| Age at First Successful Extubation | Defined as age of extubation with infant remaining extubated for more than 24 hours. | From birth to until 36 weeks postmenstrual age |
| Measure | Description | Time Frame |
|---|---|---|
| Survival | From the time of randomization up to 36 weeks corrected age, or until the time of discharge or death | |
| Total Duration of Mechanical Ventilation | From the time of first intubation until the last extubation, up to 36 weeks corrected age |
| Measure | Description | Time Frame |
|---|---|---|
| Number of Infants With Pulmonary Hemorrhage | From enrollment until 36 weeks postmenstrual age, discharge or death | |
| Number of Infants With Necrotizing Enterocolitis | From enrollment until 36 weeks postmenstrual age, discharge or death |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Eduardo Bancalari, M.D. | University of Miami | Principal Investigator |
| Nelson Claure, M.Sc., Ph.D. | University of Miami | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| NICU, Holtz Children's Hospital, Jackson Health System | Miami | Florida | 33136 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 29519541 | Derived | Amaro CM, Bello JA, Jain D, Ramnath A, D'Ugard C, Vanbuskirk S, Bancalari E, Claure N. Early Caffeine and Weaning from Mechanical Ventilation in Preterm Infants: A Randomized, Placebo-Controlled Trial. J Pediatr. 2018 May;196:52-57. doi: 10.1016/j.jpeds.2018.01.010. Epub 2018 Mar 6. |
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87 infants were enrolled. Of these, 1 died before randomization. 86 infants were randomized and assigned an intervention arm.
Recruitment was conducted at the Holtz Children's Hospital newborn intensive care unit of Jackson Health System/University of Miami Medical Center from January 2013 to October 2015.
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| ID | Title | Description |
|---|---|---|
| FG000 | Caffeine Arm | Subjects randomized to this arm will receive blinded Caffeine citrate. Caffeine citrate: Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| FG001 | Placebo Arm | Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). Normal saline: Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Caffeine Arm | Subjects randomized to this arm will receive blinded Caffeine citrate. Caffeine citrate: Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Age at First Successful Extubation | Defined as age of extubation with infant remaining extubated for more than 24 hours. | Posted | Median | Inter-Quartile Range | days | From birth to until 36 weeks postmenstrual age |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Caffeine Arm | Subjects randomized to this arm will receive blinded Caffeine citrate. Caffeine citrate: Enrolled subjects will be randomized to receive a study drug consisting of either blinded Caffeine citrate. Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Seizures | Nervous system disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Eduardo Bancalari M.D., Director Division of Neonatology | University of Miami | 3055856408 | ebancalari@miami.edu |
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| ID | Term |
|---|---|
| D047928 | Premature Birth |
| D001049 | Apnea |
| D012131 | Respiratory Insufficiency |
| D001997 | Bronchopulmonary Dysplasia |
| ID | Term |
|---|---|
| D007752 | Obstetric Labor, Premature |
| D007744 | Obstetric Labor Complications |
| D011248 | Pregnancy Complications |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
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| ID | Term |
|---|---|
| C026189 | caffeine citrate |
| D000077330 | Saline Solution |
| ID | Term |
|---|---|
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
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|
| Normal saline | Other | Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
|
| Total Duration of Oxygen Supplementation | From the time of first initiation until the last day of oxygen supplementation, up to 36 weeks corrected age |
| Number of Infants With Bronchopulmonary Dysplasia (BPD) | BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | Evaluated at 36 weeks corrected postmenstrual age |
| Survival Without BPD | Discharge alive without BPD. BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | From the time of randomization until 36 weeks corrected age, discharge or death |
| Number of Infants With Septicemia | Septicemia defined as positive blood culture | From enrollment until 36 weeks postmenstrual age, discharge or death |
| Number of Infants With Severe Intraventricular Hemorrhage | Severe intraventricular hemorrhage defined as grade III or higher | From enrollment until 36 weeks postmenstrual age, discharge or death |
| Number of Infants With Severe Retinopathy of Prematurity | Severe retinopathy of prematurity defined as stage 3 or higher | From enrollment until 36 weeks postmenstrual age, discharge or death |
| BG001 | Placebo Arm | Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). Normal saline: Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
| BG002 | Total | Total of all reporting groups |
| hours |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| Gestational age | Median | Inter-Quartile Range | weeks |
|
| Birth weight | Median | Inter-Quartile Range | grams |
|
| Fraction of inspired oxygen at enrollment | Median | Inter-Quartile Range | oxygen fraction |
|
| Mean airway pressure at enrollment | Median | Inter-Quartile Range | centimeters of water |
|
| OG001 | Placebo Arm | Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). Normal saline: Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. |
|
|
| Secondary | Survival | Posted | Count of Participants | Participants | From the time of randomization up to 36 weeks corrected age, or until the time of discharge or death |
|
|
|
| Secondary | Total Duration of Mechanical Ventilation | Infants alive at 36 weeks postmenstrual age | Posted | Median | Inter-Quartile Range | days | From the time of first intubation until the last extubation, up to 36 weeks corrected age |
|
|
|
| Secondary | Total Duration of Oxygen Supplementation | Infants alive at 36 weeks postmenstrual age | Posted | Median | Inter-Quartile Range | days | From the time of first initiation until the last day of oxygen supplementation, up to 36 weeks corrected age |
|
|
|
| Secondary | Number of Infants With Bronchopulmonary Dysplasia (BPD) | BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | Infants alive at 36 weeks postmenstrual age | Posted | Count of Participants | Participants | Evaluated at 36 weeks corrected postmenstrual age |
|
|
|
| Secondary | Survival Without BPD | Discharge alive without BPD. BPD defined as need for oxygen for at least 28 days and at 36 weeks post-menstrual age. | Posted | Count of Participants | Participants | From the time of randomization until 36 weeks corrected age, discharge or death |
|
|
|
| Other Pre-specified | Number of Infants With Pulmonary Hemorrhage | Posted | Count of Participants | Participants | From enrollment until 36 weeks postmenstrual age, discharge or death |
|
|
|
| Other Pre-specified | Number of Infants With Necrotizing Enterocolitis | Posted | Count of Participants | Participants | From enrollment until 36 weeks postmenstrual age, discharge or death |
|
|
|
| Other Pre-specified | Number of Infants With Septicemia | Septicemia defined as positive blood culture | Posted | Count of Participants | Participants | From enrollment until 36 weeks postmenstrual age, discharge or death |
|
|
|
| Other Pre-specified | Number of Infants With Severe Intraventricular Hemorrhage | Severe intraventricular hemorrhage defined as grade III or higher | Posted | Count of Participants | Participants | From enrollment until 36 weeks postmenstrual age, discharge or death |
|
|
|
| Other Pre-specified | Number of Infants With Severe Retinopathy of Prematurity | Severe retinopathy of prematurity defined as stage 3 or higher | Posted | Count of Participants | Participants | From enrollment until 36 weeks postmenstrual age, discharge or death |
|
|
|
| 9 |
| 41 |
| 0 |
| 41 |
| 0 |
| 41 |
| EG001 | Placebo Arm | Subjects randomized to this arm will receive blinded Placebo (equivalent volume of normal saline). Normal saline: Enrolled subjects will be randomized to receive a study drug consisting of blinded Placebo (equivalent volume of normal saline). Randomization and study drug preparation will be done by the NICU pharmacy. Investigators and clinicians will be blinded to the assigned drug. After randomization, an initial loading dose of 20 mg/Kg of study drug will be followed by a 5 mg/Kg/day maintenance dose. The assigned study drug will be administered intravenous or orally as determined by the clinical team. Infants will continue to receive the study drug until 12 hours prior to the first elective extubation. | 5 | 42 | 0 | 42 | 0 | 41 |
| Tachycardia | Cardiac disorders | Non-systematic Assessment |
|
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| D000091642 | Urogenital Diseases |
| D012120 | Respiration Disorders |
| D012140 | Respiratory Tract Diseases |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D055397 | Ventilator-Induced Lung Injury |
| D055370 | Lung Injury |
| D008171 | Lung Diseases |
| D007235 | Infant, Premature, Diseases |
| D007232 | Infant, Newborn, Diseases |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |