Patent Ductus Arteriosus
Conditions
Keywords
Patent ductus arteriosus, Respiratory outcome
Brief summary
The investigators propose the present study with the following aims: * to determine whether early patent ductus arteriosus (PDA) treatment with ibuprofen treatment at the onset of clinical symptoms is superior to late ibuprofen treatment only when symptoms of a hemodynamically significant PDA are present in the evolution of bronchopulmonary dysplasia (BPD) defined as duration of supplemental oxygen exposure during the first 28 days * to determine whether early PDA treatment with ibuprofen will be superior to late treatment with ibuprofen in efficacy of PDA closure, need for rescue therapy, need for PDA ligation and incidence of major complications of prematurity. Hypothesis: Early pharmacologic closure of PDA with ibuprofen will improve respiratory course and reduce BPD as reflected by a reduction in duration of supplemental oxygen during the first 28 days of age vs. late pharmacologic treatment with ibuprofen. Outcome variables: The primary outcome of this study is the number of days spent on supplemental oxygen by each infant during the first 28 days. Other outcomes to be determined between groups include: * Mortality * Other respiratory variables: total days on supplemental oxygen, days on mechanical ventilation, oxygen dependence at 36 weeks post menstrual age, age at final extubation. * Other respiratory complications: pneumothorax, pulmonary interstitial emphysema, need for high frequency ventilation, pulmonary hypertension * Efficacy of PDA closure: number of courses of medication required, need for ligation * Other neonatal complications: intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intestinal perforation, sepsis, renal dysfunction (oliguria, elevated creatinine) * Time to achieving full enteral feedings, time to regain birth weight, weight at discharge. * Length of hospital stay
Detailed description
Study terminated when intravenous (IV) ibuprofen withdrawn for both clinical and research use.
Interventions
DRUGEarly ibuprofen
IBUPROFEN SCHEDULE: initial dose 10 mg/kg, then 2 doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Initial therapy is blinded. At PDA diagnosis, infants randomized to early treatment receive blinded ibuprofen. Infants randomized to late treatment receive blinded placebo. Hemodynamically significant PDA criteria: SIGNS OF PDA + pulmonary hemorrhage OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (due to PDA) defined as at least two of the following: Need for supplemental O2 \> 50%; need IMV \>40; need for PIP \> 20; or need for HFOV. Once hemodynamically significant PDA criteria met, if echo is positive, infants from both groups can receive open label ibuprofen.
OTHERLate ibuprofen expectant group (placebo)
Drug: Late ibuprofen expectant group (placebo): DOSING SCHEDULE: At PDA diagnosis infants randomized to late ibuprofen expectant group will receive blinded placebo. If hemodynamically significant PDA develops, infants now receive open label ibuprofen at an initial dose of 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Signs of a hemodynamically significant PDA include: SIGNS OF PDA + pulmonary hemorrhage ALONE OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (due PDA) defined as at least 2 of the following settings: Need for supplemental O2 \> 50%; need IMV \>40; need for PIP \> 20; or need for HFOV.
Sponsors
H. Lundbeck A/S
University of Miami
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Days to 14 Days
Healthy volunteers
No
Inclusion criteria
* Inborn patients at JHS hospitals (admitted to the NICU at JMH within the first 72 hrs of age * BW 500-1250 grams * 23-32 wks gestational age * \> 1d but \< 14d of age.
Exclusion criteria
* Major congenital malformations * Proven sepsis (positive blood culture) * Contraindications to the use of Ibuprofen or Indomethacin * Terminal condition, not expected to survive beyond 48 h * Infants born excessively SGA(3 S.D. below the mean for GA) * Infants with initial PDA presentation that is hemodynamically significant
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Days Spent on Supplemental Oxygen During the First 28 Days. | 28 days of life |
Secondary
| Measure | Time frame |
|---|---|
| Number of Participants on Oxygen at 36 Weeks Postmenstrual Age | at 36 weeks postmenstrual age |
Countries
United States
Participant flow
Recruitment details
Recruitment was initiated on 01/02/08; the final patient was recruited on 7/26/10. Patients were enrolled at Jackson Memorial Hospital. Study was terminated early due to lack of availability of IV ibuprofen due to manufacturer's recall.
Pre-assignment details
179 subjects had consents obtained. Of these, 6 consents were withdrawn and 68 enrolled subjects were not randomized because they met exclusion criterion before randomization: hemodynamically significant PDA (n=10), absence of PDA (n=55) and other reasons (n=3). Therefore 105 enrolled subjects were randomized into 1 of 2 treatment arms.
Participants by arm
| Arm | Count |
|---|---|
| Early Ibuprofen Drug: Early ibuprofen IBUPROFEN DOSING SCHEDULE: At the diagnosis of PDA, infants randomized to early treatment will receive blinded ibuprofen initial dose 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Initial therapy will be blinded. This group will then be eligible to receive unblended, open label ibuprofen for a hemodynamically significant PDA include: SIGNS OF PDA + Presence of significant pulmonary hemorrhage ALONE OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (not due to something other than PDA) defined as at least two of the following respirator settings: Need for supplemental O2 \> 50%; need IMV \>40; need for PIP \> 20; or need for HFOV.
Early ibuprofen : IBUPROFEN DOSING SCHEDULE: initial dose 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Initial therapy will be blinded. At the diagnosis of PDA, infants randomized to early treatment w | 54 |
| Late Ibuprofen Expectant Group Drug: Late ibuprofen expectant group
IBUPROFEN DOSING SCHEDULE: At the diagnosis of PDA, infants randomized to late ibuprofen expectant group will receive blinded placebo. If criteria of a hemodynamically significant PDA develop, infants from this group can now receive open label ibuprofen at an initial dose of 10 mg/kg, then two doses 5 mg/kg each, after 24 and 48 h, slow IV infusion. Signs of a hemodynamically significant PDA include: SIGNS OF PDA + Presence of significant pulmonary hemorrhage ALONE OR SIGNS OF PDA +: Pulmonary edema, plus a large heart on CXR + one of the following: Hypotension, Respiratory failure (not due to something other than PDA) defined as at least two of the following respirator settings: Need for supplemental O2 \> 50%; need IMV \>40; need for PIP \> 20; or need for HFOV. Infants who had received placebo will be have ibuprofen for the first time (thus, late ibuprofen or expectant).
Late ibuprofen expectant group : Other: Late Ibuprofen expectant | 51 |
| Total | 105 |
Baseline characteristics
| Characteristic | Early Ibuprofen | Late Ibuprofen Expectant Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 54 Participants | 51 Participants | 105 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment United States | 54 participants | 51 participants | 105 participants |
| Sex: Female, Male Female | 29 Participants | 21 Participants | 50 Participants |
| Sex: Female, Male Male | 25 Participants | 30 Participants | 55 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 54 | 0 / 51 |
| serious Total, serious adverse events | 0 / 54 | 0 / 51 |
Outcome results
Primary
Days Spent on Supplemental Oxygen During the First 28 Days.
Time frame: 28 days of life
Population: The number of participants for analysis was determined from all subjects who completed the study intervention at 28 days of age and had complete data on the primary endpoint of oxygen days during the first 28 days. Analysis was done on intention to treat basis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Early Ibuprofen | Days Spent on Supplemental Oxygen During the First 28 Days. | 21 days |
| Late Ibuprofen Expectant Group | Days Spent on Supplemental Oxygen During the First 28 Days. | 19 days |
Comparison: Null hypothesis: Oxygen duration (days) during the first 28 days will be equal between treatment arms.p-value: 0.85895% CI: [4, 36]Wilcoxon (Mann-Whitney)
Secondary
Number of Participants on Oxygen at 36 Weeks Postmenstrual Age
Time frame: at 36 weeks postmenstrual age
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Early Ibuprofen | Number of Participants on Oxygen at 36 Weeks Postmenstrual Age | 17 participants |
| Late Ibuprofen Expectant Group | Number of Participants on Oxygen at 36 Weeks Postmenstrual Age | 16 participants |
Comparison: null hypothesis: The proportion of subjects on O2 at 36 wk PMA will be equal between treatment arms.p-value: 0.895% CI: [0.393, 2.309]Cochran-Mantel-Haenszel