Bronchopulmonary Dysplasia, Patent Ductus Arteriosus, Preterm Infant
Conditions
Keywords
patent ductus arteriosus, acetaminophen, ibuprofen, bronchopulmonary dysplasia, mechanical ventilation
Brief summary
The purpose of the present study is to determine whether treatment of hemodynamically significant patent ductus arteriosus with a combined therapy of intravenous Ibuprofen and oral acetaminophen has higher success rate in closing the ductus arteriosus than a standard treatment strategy of using intravenous ibuprofen alone among preterm infants.
Detailed description
The primary objectives of the study are to confirm the safety of oral acetaminophen in extremely low birth infants, given concomitantly with intravenous ibuprofen and also to determine its efficacy in significantly increasing the rates of ductal closure when compared to only intravenous ibuprofen therapy. Hence primary outcome variable include patent ductus arteriosus closure success rate, based on the 2-D transthoracic echocardiographic evidence. This study is a single center, randomized, double blinded, placebo controlled trial. Preterm infants with gestational age of with a gestational age ≤27 6/7 weeks by the best obstetric estimate are eligible for enrollment. For randomization, the study population will be stratified to two subgroups based on gestational age (GA ≤24 weeks and \> 25 weeks). Randomization will occur by using computer generated random sequence, using a 4-block design, with 1:1 parallel allocation. Allocations include treatment and control arm. Treatment arm will receive combination of intravenous ibuprofen and oral acetaminophen, while control arm will receive intravenous Ibuprofen and oral placebo.
Interventions
DRUGIbuprofen and acetaminophen
Intravenous ibuprofen given concomitantly with oral acetaminophen
Intravenous ibuprofen given concomitantly with oral placebo
Sponsors
University of South Alabama
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
5 Days to 21 Days
Healthy volunteers
No
Inclusion criteria
1. Preterm infant ≤27 6/7 2. Written parental consent is obtained 3. Infant requires respiratory support 4. diagnosis of a persistent patent ductus arteriosus after 5 days of age, (defined as at least two of the following: 1. Ductus size ≥ 1.5 mm 2. Maximum flow velocity through the ductus ≤ 2 m/s 3. Left atrium to aorta ratio ≥ 1.4 4. Wide pulse pressure 5. B-type natriuretic peptide (BNP) 5. Attending neonatologist made decision to treat patent ductus arteriosus
Exclusion criteria
1. No parental consent 2. Infants \> 21days of postnatal age 3. Congenital anomalies such as cardiac or multiple anomalies 4. Infection (e.g., septicemia, pneumonia) 5. Bleeding disorder or platelet count\< 50,000/ml 6. Acute kidney injury (AKI)defined as oliguria (urine output\< 0.5 ml/kg/hr for 16hrs) and/or serum creatinine \> 1.5 mg/dl 7. Elevated liver enzymes (\>2 fold from upper normal limits) 8. Pulmonary hypertension or right to left shunt through the ductus arteriosus 9. Diagnosis of necrotizing enterocolitis 10. Unable to tolerate oral medications at the time of enrollment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Participants With Ductus Arteriosus Closure/Constriction | 24-48 hours after the completion of study intervention | Ductal closure/constriction rate as defined based on the echocardiographic findings. Ductal closure/constriction will be defined as the complete closure of ductus or ductal diameter \<1 mm |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention | 24-48 hours after the completion of study intervention | Echocardiographic parameters including ductal size (PDA size in mm), Left atrium to aortic root ratio, ductal velocity, descending aortic diastolic flow, before and after the intervention. Between the group and within the group comparison |
| Ventilatory Settings Before and After the Study Intervention | 24-48 hours after the completion of study intervention | Ventilator parameters including Fio2, Mean airway pressure, Peak Inspiratory pressure, PEEP, and ventilatory rate oxygenation indices including Oxygenation index and Respiratory Severity score before and after intervention |
| Proportion of Participants With Liver Injury | 24-48 hours after the completion of study intervention | liver enzymes compared before and after the study intervention; if any significant elevation of liver enzymes from baseline, the participant classified as having liver injury |
| Proportion of Participants With Renal Injury | 24-48 hours after the completion of study intervention | Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention are compared. Participants exhibiting significant elevation BUN and S creatine, are classified as having renal injury |
| Proportion of Participants With Hematological Adverse Events | 24-48 hours after the completion of study intervention | Hematocrit and platelet counts compared before and after the study intervention; if any significant alteration from baseline, the participant classified as having hematological adverse event, |
| Total Number of Days of Mechanical Ventilation | from randomization until discharge/40 weeks post menstrual age | The total number of days on mechanical ventilation are counted as total duration of conventional mechanical ventilation plus high frequency ventilatory days |
| Total Number of Days of Need for Supplemental Oxygen | from randomization until discharge/40 weeks post menstrual age | Cumulative days on any supplemental O2 (including Mechanical ventilation., noninvasive ventilation, nasal cannula support) calculated from randomization until 4 weeks of postmenstrual age |
| Duration of Noninvasive Ventilation | from randomization until discharge/40 weeks post menstrual age | Total cumulative days on noninvasive ventilation, including NIPPV and nasal CPAP, |
| Proportion of Participants With Persistence of Ductus-needing Pharmacological Treatment | from randomization until discharge/40 weeks post menstrual age | Proportion of participants in each group requiring open label treatment with pharmacological agents for ductal closure, e.g. IV Ibuprofen or IV Acetaminophen or IV indomethacin therapies, as decided by the treating physician |
| Proportion of Participants Requiring Surgical Ligation of PDA | from randomization until discharge/40 weeks post menstrual age | Proportion of participants in each group requiring surgical ligation of persistent PDA for definitive surgical closure |
| Proportion of Participants Developing Bronchopulmonary Dysplasia | at 36 weeks post menstrual age | Proportion of participants diagnosed to have BPD based supplemental O2 requirement at 36 weeks' postmenstrual age |
| Percentage of Infants Requiring Home Oxygen Therapy | at discharge/40 weeks post menstrual age | Proportion of participants in each group requiring home-based supplemental O2 therapy following the initial discharge from hospital. |
| Proportion of Participants Developing Death Before Discharge | until discharge/40 weeks post menstrual age | Proportion of participants in each group developing in-hospital death prior to 40 weeks of postmenstrual age. |
| Time to Achieve Full Enteral Feeding | from birth until discharge/40 weeks post menstrual age | Duration days during the postnatal period required to achieve an enteral feeding volume of 120 ml/kg/day. |
| Total Days on Total Parenteral Nutrition | from birth until discharge/40 weeks post menstrual age | Cumulative days of receiving total parental nutrition from birth until the participant is discharged or reached postmenstrual age of 40 weeks |
| Proportion of Participants With Retinopathy of Prematurity | from birth until discharge/40 weeks post menstrual age | Proportion of participants in each group diagnosed to have retinopathy of prematurity |
| Proportion of Participants Developing Spontaneous Intestinal Perforation | from randomization until discharge/40 weeks post menstrual age | Proportion of participants developing or having the diagnosis of spontaneous intestinal perforation from randomization until discharge or 40 weeks' Postmenstrual age |
| Proportion of Participants Developing Necrotizing Enterocolitis | from randomization until discharge/40 weeks post menstrual age | Proportion of participants in each group with the diagnosis of medical or surgical Necrotizing Enterocolitis |
| Proportion of Participants Developing Gastrointestinal Hemorrhage | from randomization until discharge/40 weeks post menstrual age | Proportion of participants in each group developing gastrointestinal hemorrhage following randomization until discharge or postmenstrual age of 40 weeks |
| Proportion of Participants Developing Late Onset Sepsis | from randomization until discharge/40 weeks post menstrual age | Proportion of participants diagnosed to have either probable sepsis with minimum of 7 days of antibiotic therapy or culture proven sepsis |
| Length of Hospital Stay | from birth until discharge/40 weeks post menstrual age | Total duration (in days ) of hospital stay |
| Proportion of Participants With Periventricular Leukomalacia | from randomization until discharge/40 weeks post menstrual age | Proportion of participants in each group with the evidence of periventricular leukomalacia on neurosonography |
Countries
United States
Contacts
STUDY_DIRECTORFabien Eyal, MD
University of South Alabama
Participant flow
Recruitment details
Overall screening for the study enrollment started 12/15/2018. Screening was continued until 10/30/2020. The study was conducted at the Neonatal Intensive Care Unit
Participants by arm
| Arm | Count |
|---|---|
| Ibuprofen and Acetaminophen Arm (Intervention Arm) ibuprofen and acetaminophen will be administered concomitantly. Ibuprofen will be administered through intravenous route. The dose of ibuprofen will be the standard dosing regimen used in our unit: dosing based on the postnatal age. For Infants \> 108 h of postnatal age: 18 mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Acetaminophen will be administered as oral formulation. Acetaminophen is given at a dose of 15 mg/Kg/dose, q 6 hours, for 3 days (total of 12 doses).
Ibuprofen and acetaminophen: Intravenous ibuprofen given concomitantly with oral acetaminophen | 1 |
| Ibuprofen and Placebo Arm (Control Arm) ibuprofen and placebo will be administered concomitantly. Ibuprofen will be administered through intravenous route. The dose of ibuprofen will be the standard dosing regimen used in our unit: dosing based on the postnatal age. For Infants \> 108 h of postnatal age: 18 mg/kg/dose loading dose followed by 9 mg/kg/dose, two doses at q24 intervals, started 24 h after the loading dose. Placebo will be sterile water, with similar volume and color as acetaminophen, will be given through the oro-gastric tube, for three days at 6 h intervals.
Ibuprofen and placebo: Intravenous ibuprofen given concomitantly with oral placebo | 0 |
| Total | 1 |
Baseline characteristics
| Characteristic | Ibuprofen and Acetaminophen Arm (Intervention Arm) | Ibuprofen and Placebo Arm (Control Arm) | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| PDA size | 1.5 mm | — | 1.5 mm |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | — | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | — | 1 Participants |
| Region of Enrollment United States | 1 participants | — | 1 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 1 | 0 / 0 |
| other Total, other adverse events | 1 / 1 | 0 / 0 |
| serious Total, serious adverse events | 0 / 1 | 0 / 0 |
Outcome results
Primary
Ductus Arteriosus Closure/Constriction Rate
Ductal closure/constriction rate as defined based on the echocardiographic findings. Ductal closure/constriction will be defined as the complete closure of ductus or ductal diameter \<1 mm
Time frame: 24-48 hours after the completion of study intervention
Population: None were enrolled for the control arm
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Ibuprofen and Acetaminophen Arm (Intervention Arm) | Ductus Arteriosus Closure/Constriction Rate | 0 Participants |
| Ibuprofen and Placebo Arm (Control Arm) | Ductus Arteriosus Closure/Constriction Rate | 0 Participants |
Secondary
Days on Total Parenteral Nutrition
Time frame: from birth until discharge/40 weeks post menstrual age
Secondary
Death Before Discharge
Time frame: until discharge/40 weeks post menstrual age
Secondary
Duration of Noninvasive Ventilation
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Echocardiographic Patent Ductus Arteriosus Parameters Before and After the Study Intervention
Time frame: 24-48 hours after the completion of study intervention
Secondary
Length of Hospital Stay
Time frame: from birth until discharge/40 weeks post menstrual age
Secondary
Percentage of Infants Requiring Home Oxygen Therapy
Time frame: at discharge/40 weeks post menstrual age
Secondary
Rate of Bronchopulmonary Dysplasia
Time frame: at 36 weeks post menstrual age
Secondary
Rate of Gastrointestinal Hemorrhage
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Hematological Adverse Events
Hematocrit and platelets before and after the study intervention
Time frame: 24-48 hours after the completion of study intervention
Secondary
Rate of Late Onset Sepsis
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Liver Injury
liver enzymes before and after the study intervention
Time frame: 24-48 hours after the completion of study intervention
Secondary
Rate of Necrotizing Enterocolitis
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Periventricular Leukomalacia
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Persistence of Ductus-needing Pharmacological Treatment
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Renal Injury
Blood urea nitrogen (BUN) and serum creatinine before and after the study intervention
Time frame: 24-48 hours after the completion of study intervention
Secondary
Rate of Spontaneous Intestinal Perforation
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Rate of Surgical Ligation of PDA
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Retinopathy of Prematurity
Time frame: from birth until discharge/40 weeks post menstrual age
Secondary
Time to Achieve Full Enteral Feeding
Time to achieve 120 ml/kg/day of enteral feeding
Time frame: from birth until discharge/40 weeks post menstrual age
Secondary
Total Number of Days of Mechanical Ventilation
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Total Number of Days of Need for Supplemental Oxygen
Time frame: from randomization until discharge/40 weeks post menstrual age
Secondary
Ventilatory Settings Before and After the Study Intervention
Time frame: 24-48 hours after the completion of study intervention