Ureaplasma Infections
Conditions
Keywords
Ureaplasma parvum, Ureaplasma urealyticum, prematurity, bronchopulmonary dysplasia, azithromycin
Brief summary
The purpose of this study is to determine whether intravenous azithromycin is effective in eradicating Ureaplasma respiratory tract infection in preterm infants born at 24 to 28 weeks gestation.
Detailed description
The study design will be a double-blind, placebo-controlled clinical trial to test the efficacy and safety of azithromycin 20 mg/kg x 3 days to eradicate Ureaplasma spp from the respiratory tract of preterm infants 24 weeks 0 days to 28 weeks 6 days gestation exposed to positive pressure ventilation. The primary outcome will be survival with microbiological eradication of Ureaplasma defined as survival to discharge or transfer with 3 negative cultures obtained post-therapy. Secondary outcomes will include physiologic BPD at 36 weeks post-menstrual age (PMA), overall mortality, incidence of co-morbidities of prematurity such as intraventricular hemorrhage, periventricular leukomalacia, necrotizing enterocolitis, bacterial and fungal nosocomial infection, pulmonary air leak, patent ductus arteriosus, retinopathy of prematurity, number of days of positive pressure ventilation, number of days of oxygen supplementation, use of postnatal steroids, and use of non-study antibiotics. At 6 and 18 months adjusted age, a pulmonary outcome questionnaire will be administered by phone or in person interview. At 18-22 months adjusted age, neurodevelopmental outcomes will be assessed by 1) Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III); 2) Amiel-Tison neurologic examination; 3) Gross Motor Function Classification System; and 4) medical record review for hearing impairment with or without amplification and vision impairment (vision \<20/200).
Interventions
DRUGAzithromycin
Azithromycin intravenous 20 mg/kg every 24 h x 3 days
DRUGPlacebo
D5W
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Mercy Medical Center
Johns Hopkins University
University of Virginia
University of Alabama at Birmingham
Christiana Care Health Services
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Hours to 72 Hours
Healthy volunteers
No
Inclusion criteria
* Gestational age 24 weeks 0 days-28weeks 6 days by best obstetrical estimate * \<72 h age * Positive pressure ventilation for at least 1 hour duration during the first 72 hours of life * Presence of indwelling intravenous line for drug administration
Exclusion criteria
* Any patient judged to be non-viable or for whom withdrawal of life support is planned * Patients with major lethal congenital anomalies * Triplets or higher order multiples * Patients delivered for maternal indications (low risk of Ureaplasma colonization) * Patients with EKG QT interval corrected for heart rate (Qtc) ≥ 450 ms * Patients with significant hepatic impairment (direct bilirubin \>1.5 mg/dL) * Patients exposed to other systemic macrolide * Patients with clinically suspected Ureaplasma central nervous system (CNS) infection or other confirmed bacterial/viral infection * Patients participating in other clinical trials involving investigational products.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Bacterial clearance (eradication) will be defined as 3 negative cultures obtained 2 and 5 days post-third dose and 21 d of age. Survival is defined as survival at time of discharge or transfer from the neonatal intensive care unit (NICU). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Pulmonary Impairment | 6-26 months | Parent report of recurrent wheezing and/or chronic cough |
| Number of Participants Who Died | 22-26 months | Number of Participants who died from any cause |
| Duration of Positive Pressure Support | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support. |
| Duration of Oxygen Supplementation | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Cumulative number of days of receipt of supplemental oxygen |
| Number of Participants Who Experienced Air Leaks | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray |
| Number of Participants Who Received Postnatal Steroids | 36 weeks | Receipt of steroid medications (hydrocortisone, dexamethasone) |
| Number of Participants Who Received Non-Study Antibiotics | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Received Non-study antibiotics following study drug intervention period. |
| Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations | Study day 1-day 7 | Number of serum azithromycin concentrations that fell outside the 90% prediction interval determined by 200 simulated replicates based on the population PK of azithromycin in preterm infants. |
| Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age | 36 weeks post menstrual age (one month prior to due date) | Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring |
| Number of Participants With Death or Neurodevelopmental Impairment | 22-26 months | Neurodevelopmental impairment will be assigned if any of the following are present at 22-26 months adjusted age: moderate to severe cerebral palsy, bilateral blindness, bilateral hearing impairment requiring amplification, Gross Motor Function Classification System score ≥ 2, or Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III) cognitive or motor score \<70. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Infections During the NICU Hospitalization | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine) |
| Number of Participants With Severe Intraventicular Hemorrhage (IVH) | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Number of Participants with Grade III or IV IVH confirmed by cranial ultrasound |
| Number of Participants With Periventricular Leukomalacia (PVL) | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | The number of Participants with cranial ultrasound confirmed PVL |
| Number of Participants With Patent Ductus Arteriosus (PDA) | 14 days | Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure. |
| Number of Participants With Cardiac Arrhythmia | 3 days | Number of Participants with EKG evidence of prolonged QT (QTc \> 450 ms) |
| Number of Participants With Threshold Retinopathy of Prematurity (ROP) | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination |
| Number of Participants With Necrotizing Enterocolitis (NEC) | Participants will be followed for the duration of hospital stay, an expected average of 10 weeks | Necrotizing enterocolitis ≥ Bell Stage II by radiographic and clinical criteria. |
Countries
United States
Participant flow
Recruitment details
Recruitment period July 1, 2013- August 31, 2016 at 7 U.S. hospital Neonatal Intensive Care Units (NICUs).
Participants by arm
| Arm | Count |
|---|---|
| Placebo (5% Dextrose) Placebo
Placebo: D5W 10 ml/kg every 24 h x 3 days | 61 |
| Azithromycin Azithromycin intravenous (2 mg/ml) 20 mg/kg every 24h x 3 days
Azithromycin: Azithromycin intravenous 20 mg/kg every 24 h x 3 days | 60 |
| Total | 121 |
Baseline characteristics
| Characteristic | Placebo (5% Dextrose) | Total | Azithromycin |
|---|---|---|---|
| Age, Continuous | 26.2 weeks gestation STANDARD_DEVIATION 1.4 | 26.2 weeks gestation STANDARD_DEVIATION 1.4 | 26.2 weeks gestation STANDARD_DEVIATION 1.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 61 Participants | 119 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 43 Participants | 64 Participants | 21 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 5 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 51 Participants | 36 Participants |
| Region of Enrollment United States | 61 Participants | 121 Participants | 60 Participants |
| Sex: Female, Male Female | 29 Participants | 63 Participants | 34 Participants |
| Sex: Female, Male Male | 32 Participants | 58 Participants | 26 Participants |
| Ureaplasma-positive | 25 Participants | 44 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 6 / 61 | 5 / 60 |
| other Total, other adverse events | 51 / 61 | 51 / 60 |
| serious Total, serious adverse events | 39 / 61 | 44 / 60 |
Outcome results
Primary
Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma
Bacterial clearance (eradication) will be defined as 3 negative cultures obtained 2 and 5 days post-third dose and 21 d of age. Survival is defined as survival at time of discharge or transfer from the neonatal intensive care unit (NICU).
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma | 37 Participants |
| Azithromycin | Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma | 55 Participants |
p-value: <0.000195% CI: [2.53, 22.27]Cochran-Mantel-Haenszel
Secondary
Duration of Oxygen Supplementation
Cumulative number of days of receipt of supplemental oxygen
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (5% Dextrose) | Duration of Oxygen Supplementation | 68 days |
| Azithromycin | Duration of Oxygen Supplementation | 73 days |
p-value: 0.9495% CI: [-15, 26]Wilcoxon test after multiple outputation
Secondary
Duration of Positive Pressure Support
Combined number of days receiving mechanical ventilation plus non-invasive modes of positive pressure support.
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo (5% Dextrose) | Duration of Positive Pressure Support | 36 days |
| Azithromycin | Duration of Positive Pressure Support | 39 days |
p-value: 0.88Wilcoxon (Mann-Whitney)
Secondary
Number of Participants Who Died
Number of Participants who died from any cause
Time frame: 22-26 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants Who Died | 6 Participants |
| Azithromycin | Number of Participants Who Died | 5 Participants |
p-value: 1Fisher Exact
Secondary
Number of Participants Who Experienced Air Leaks
Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Population: The participants who had air leak at baseline (prior to randomization) were excluded from analysis (3 placebo and 5 azithromycin).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants Who Experienced Air Leaks | 4 Participants |
| Azithromycin | Number of Participants Who Experienced Air Leaks | 7 Participants |
p-value: 0.49Fisher Exact
Secondary
Number of Participants Who Received Non-Study Antibiotics
Received Non-study antibiotics following study drug intervention period.
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants Who Received Non-Study Antibiotics | 14 Participants |
| Azithromycin | Number of Participants Who Received Non-Study Antibiotics | 8 Participants |
p-value: 0.18Generalized Estimating Equations
Secondary
Number of Participants Who Received Postnatal Steroids
Receipt of steroid medications (hydrocortisone, dexamethasone)
Time frame: 36 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants Who Received Postnatal Steroids | 14 Participants |
| Azithromycin | Number of Participants Who Received Postnatal Steroids | 15 Participants |
p-value: 0.8895% CI: [0.44, 2.63]Cochran-Mantel-Haenszel
Secondary
Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age
Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring
Time frame: 36 weeks post menstrual age (one month prior to due date)
Population: Participants who survived until assessment timepoint 36 weeks post menstrual age (1 month before due date)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age | 18 Participants |
| Azithromycin | Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age | 25 Participants |
p-value: 0.2895% CI: [-0.08, 0.29]Generalized Estimating Equations
Secondary
Number of Participants With Death or Neurodevelopmental Impairment
Neurodevelopmental impairment will be assigned if any of the following are present at 22-26 months adjusted age: moderate to severe cerebral palsy, bilateral blindness, bilateral hearing impairment requiring amplification, Gross Motor Function Classification System score ≥ 2, or Bayley Scale of Infant and Toddler Development, 3rd edition (BSID-III) cognitive or motor score \<70.
Time frame: 22-26 months
Population: Participants who died prior to the 22-26 months assessment timepoint and participants who were assessed for neurodevelopmental impairments
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Death or Neurodevelopmental Impairment | 17 Participants |
| Azithromycin | Number of Participants With Death or Neurodevelopmental Impairment | 25 Participants |
p-value: 0.11GEE
Secondary
Number of Participants With Pulmonary Impairment
Parent report of recurrent wheezing and/or chronic cough
Time frame: 6-26 months
Population: All participants enrolled and randomized in the trial
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Pulmonary Impairment | 12 Participants |
| Azithromycin | Number of Participants With Pulmonary Impairment | 15 Participants |
p-value: 0.62GEE with multiple imputation
Secondary
Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations
Number of serum azithromycin concentrations that fell outside the 90% prediction interval determined by 200 simulated replicates based on the population PK of azithromycin in preterm infants.
Time frame: Study day 1-day 7
Population: No plasma samples from placebo group were analyzed for azithromycin concentrations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Azithromycin | Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations | 4 serum conc outside predicted interval |
Other Pre-specified
Number of Participants With Cardiac Arrhythmia
Number of Participants with EKG evidence of prolonged QT (QTc \> 450 ms)
Time frame: 3 days
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Cardiac Arrhythmia | 0 Participants |
| Azithromycin | Number of Participants With Cardiac Arrhythmia | 0 Participants |
p-value: 1Fisher Exact
Other Pre-specified
Number of Participants With Infections During the NICU Hospitalization
Culture-confirmed bacterial or fungal infection based on culture from sterile site (blood, cerebral spinal fluid, or urine)
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Infections During the NICU Hospitalization | 14 Participants |
| Azithromycin | Number of Participants With Infections During the NICU Hospitalization | 8 Participants |
p-value: 0.18Generalized Estimating Equations
Other Pre-specified
Number of Participants With Necrotizing Enterocolitis (NEC)
Necrotizing enterocolitis ≥ Bell Stage II by radiographic and clinical criteria.
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Necrotizing Enterocolitis (NEC) | 5 Participants |
| Azithromycin | Number of Participants With Necrotizing Enterocolitis (NEC) | 4 Participants |
p-value: 1Fisher Exact
Other Pre-specified
Number of Participants With Patent Ductus Arteriosus (PDA)
Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.
Time frame: 14 days
Population: Participants who did not have PDA at baseline (prior to randomization). Participants with PDA at baseline were excluded from analysis (5 placebo and 5 azithromycin.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Patent Ductus Arteriosus (PDA) | 21 Participants |
| Azithromycin | Number of Participants With Patent Ductus Arteriosus (PDA) | 25 Participants |
p-value: 0.33Generalized Estimating Equations
Other Pre-specified
Number of Participants With Periventricular Leukomalacia (PVL)
The number of Participants with cranial ultrasound confirmed PVL
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Periventricular Leukomalacia (PVL) | 5 Participants |
| Azithromycin | Number of Participants With Periventricular Leukomalacia (PVL) | 4 Participants |
p-value: 1Fisher Exact
Other Pre-specified
Number of Participants With Severe Intraventicular Hemorrhage (IVH)
Number of Participants with Grade III or IV IVH confirmed by cranial ultrasound
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Population: The participants who had a Grade III or IV IVH at baseline (prior to randomization) were excluded (2 placebo and 4 Azithromycin).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Severe Intraventicular Hemorrhage (IVH) | 2 Participants |
| Azithromycin | Number of Participants With Severe Intraventicular Hemorrhage (IVH) | 7 Participants |
p-value: 0.091Fisher Exact
Other Pre-specified
Number of Participants With Threshold Retinopathy of Prematurity (ROP)
Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination
Time frame: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
Population: The number of participants who survived to receive at least 1 eye exam for retinopathy of prematurity
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo (5% Dextrose) | Number of Participants With Threshold Retinopathy of Prematurity (ROP) | 4 Participants |
| Azithromycin | Number of Participants With Threshold Retinopathy of Prematurity (ROP) | 11 Participants |
p-value: 0.05Generalized Estimating Equation