Trial Outcomes & Findings for Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants (NCT NCT01778634)

NCT ID: NCT01778634

Last Updated: 2020-11-30

Results Overview

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).

• Recruitment status: COMPLETED
• Study phase: PHASE2
• Target enrollment: 121 participants
• Primary outcome timeframe: Participants will be followed for the duration of hospital stay, an expected average of 10 weeks
• Results posted on: 2020-11-30

Participant Flow

Recruitment period July 1, 2013- August 31, 2016 at 7 U.S. hospital Neonatal Intensive Care Units (NICUs).

Participant milestones

Measure	Placebo (5% Dextrose) Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	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
Overall Study STARTED	61	60
Overall Study COMPLETED	61	60
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Trial of Intravenous Azithromycin to Eradicate Ureaplasma Respiratory Tract Infection in Preterm Infants

Baseline characteristics by cohort

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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	Total n=121 Participants Total of all reporting groups
Age, Continuous	26.2 weeks gestation STANDARD_DEVIATION 1.4 • n=5 Participants	26.2 weeks gestation STANDARD_DEVIATION 1.4 • n=7 Participants	26.2 weeks gestation STANDARD_DEVIATION 1.4 • n=5 Participants
Sex: Female, Male Female	29 Participants n=5 Participants	34 Participants n=7 Participants	63 Participants n=5 Participants
Sex: Female, Male Male	32 Participants n=5 Participants	26 Participants n=7 Participants	58 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	61 Participants n=5 Participants	58 Participants n=7 Participants	119 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 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	1 Participants n=5 Participants	0 Participants n=7 Participants	1 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	43 Participants n=5 Participants	21 Participants n=7 Participants	64 Participants n=5 Participants
Race (NIH/OMB) White	15 Participants n=5 Participants	36 Participants n=7 Participants	51 Participants n=5 Participants
Race (NIH/OMB) More than one race	2 Participants n=5 Participants	3 Participants n=7 Participants	5 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	61 Participants n=5 Participants	60 Participants n=7 Participants	121 Participants n=5 Participants
Ureaplasma-positive	25 Participants n=5 Participants	19 Participants n=7 Participants	44 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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).

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Survival And Transfer From NICU With Microbiological Eradication of Ureaplasma	37 Participants	55 Participants

SECONDARY outcome

Timeframe: 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)

Number of Participants who survived until 36 wks postmenstrual age with Physiologic defined bronchopulmonary dysplasia (BPD) based on oxygen-saturation monitoring

Outcome measures

Measure	Placebo (5% Dextrose) n=54 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=56 Participants 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
Number of Participants Who Survived Until 36 Wks Postmenstrual Age With Physiologic Defined Bronchopulmonary Dysplasia (BPD) at 36 Weeks Post Menstrual Age	18 Participants	25 Participants

SECONDARY outcome

Timeframe: 22-26 months

Population: Participants who died prior to the 22-26 months assessment timepoint and participants who were assessed for neurodevelopmental impairments

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.

Outcome measures

Measure	Placebo (5% Dextrose) n=52 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=53 Participants 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
Number of Participants With Death or Neurodevelopmental Impairment	17 Participants	25 Participants

SECONDARY outcome

Timeframe: 6-26 months

Population: All participants enrolled and randomized in the trial

Parent report of recurrent wheezing and/or chronic cough

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Pulmonary Impairment	12 Participants	15 Participants

SECONDARY outcome

Timeframe: 22-26 months

Number of Participants who died from any cause

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants Who Died	6 Participants	5 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Duration of Positive Pressure Support	36 days Interval 17.0 to 60.0	39 days Interval 19.0 to 56.0

SECONDARY outcome

Timeframe: 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

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Duration of Oxygen Supplementation	68 days Interval 33.0 to 118.0	73 days Interval 39.0 to 114.5

SECONDARY outcome

Timeframe: 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).

Any pulmonary air leak (pulmonary interstitial emphysema, pneumothorax, pneumomediastinum) confirmed by chest x-ray

Outcome measures

Measure	Placebo (5% Dextrose) n=57 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=55 Participants 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
Number of Participants Who Experienced Air Leaks	4 Participants	7 Participants

SECONDARY outcome

Timeframe: 36 weeks

Receipt of steroid medications (hydrocortisone, dexamethasone)

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants Who Received Postnatal Steroids	14 Participants	15 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants Who Received Non-Study Antibiotics	14 Participants	8 Participants

SECONDARY outcome

Timeframe: Study day 1-day 7

Population: No plasma samples from placebo group were analyzed for azithromycin 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.

Outcome measures

Measure	Placebo (5% Dextrose) Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=27 number of serum samples concentrations 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
Pharmacokinetics (PK)/Pharmacodynamics (PD) Modelling of Time Course of Azithromycin Plasma Concentrations	—	4 serum conc outside predicted interval

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Threshold ROP requiring surgical intervention as diagnosed by ophthalmologic examination

Outcome measures

Measure	Placebo (5% Dextrose) n=56 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=56 Participants 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
Number of Participants With Threshold Retinopathy of Prematurity (ROP)	4 Participants	11 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Necrotizing Enterocolitis (NEC)	5 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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)

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Infections During the NICU Hospitalization	14 Participants	8 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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).

Number of Participants with Grade III or IV IVH confirmed by cranial ultrasound

Outcome measures

Measure	Placebo (5% Dextrose) n=59 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=56 Participants 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
Number of Participants With Severe Intraventicular Hemorrhage (IVH)	2 Participants	7 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Periventricular Leukomalacia (PVL)	5 Participants	4 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 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.

Detection of PDA by cardiac echocardiogram with left to right shunting, or clinical evidence of murmur, bounding pulses, and widened pulse pressure.

Outcome measures

Measure	Placebo (5% Dextrose) n=56 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=55 Participants 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
Number of Participants With Patent Ductus Arteriosus (PDA)	21 Participants	25 Participants

OTHER_PRE_SPECIFIED outcome

Timeframe: 3 days

Number of Participants with EKG evidence of prolonged QT (QTc > 450 ms)

Outcome measures

Measure	Placebo (5% Dextrose) n=61 Participants Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 Participants 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
Number of Participants With Cardiac Arrhythmia	0 Participants	0 Participants

Adverse Events

Placebo (5% Dextrose)

Serious events: 39 serious events

Other events: 51 other events

Deaths: 6 deaths

Azithromycin

Serious events: 44 serious events

Other events: 51 other events

Deaths: 5 deaths

Serious adverse events

Measure	Placebo (5% Dextrose) n=61 participants at risk Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 participants at risk 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
Respiratory, thoracic and mediastinal disorders Respiratory Distress	9.8% 6/61 • 3 years 6 months	8.3% 5/60 • 3 years 6 months
Respiratory, thoracic and mediastinal disorders Respiratory Failure	4.9% 3/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Respiratory, thoracic and mediastinal disorders Apnea	6.6% 4/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Cardiac disorders Patent Ductus Arteriosus	19.7% 12/61 • 3 years 6 months	28.3% 17/60 • 3 years 6 months
Gastrointestinal disorders Necrotizing enterocolitis	4.9% 3/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Gastrointestinal disorders Intestinal Perforation	6.6% 4/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Gastrointestinal disorders Ileal stricture	0.00% 0/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Hepatobiliary disorders Cholestasis	8.2% 5/61 • 3 years 6 months	8.3% 5/60 • 3 years 6 months
Eye disorders Retinopathy of prematurity	5.0% 3/60 • 3 years 6 months	19.0% 11/58 • 3 years 6 months
Blood and lymphatic system disorders Anemia	9.8% 6/61 • 3 years 6 months	8.3% 5/60 • 3 years 6 months
Blood and lymphatic system disorders White blood cell count >40,000 cells/mm3	6.6% 4/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Blood and lymphatic system disorders Thrombocytopenia	3.3% 2/61 • 3 years 6 months	3.3% 2/60 • 3 years 6 months
Infections and infestations Sepsis	14.8% 9/61 • 3 years 6 months	10.0% 6/60 • 3 years 6 months
Infections and infestations Urinary tract infection	6.6% 4/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Metabolism and nutrition disorders Blood Urea Nitrogen > 60 mg/dL	6.6% 4/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Metabolism and nutrition disorders Hypercalcemia	3.3% 2/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Metabolism and nutrition disorders Hypochloremia	0.00% 0/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Metabolism and nutrition disorders Hypernatremia	3.3% 2/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Metabolism and nutrition disorders Hypokalemia	0.00% 0/61 • 3 years 6 months	3.3% 2/60 • 3 years 6 months
Metabolism and nutrition disorders Hyponatremia	1.6% 1/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months

Other adverse events

Measure	Placebo (5% Dextrose) n=61 participants at risk Placebo Placebo: D5W 10 ml/kg every 24 h x 3 days	Azithromycin n=60 participants at risk 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
Skin and subcutaneous tissue disorders IV site reaction	1.6% 1/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Skin and subcutaneous tissue disorders Rash	0.00% 0/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Gastrointestinal disorders Vomiting	1.6% 1/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Gastrointestinal disorders Gastric residual >50% volume of feed	1.6% 1/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Gastrointestinal disorders Abdominal Distension	3.3% 2/61 • 3 years 6 months	5.0% 3/60 • 3 years 6 months
Gastrointestinal disorders Loose stools	1.6% 1/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Infections and infestations Oral thrush	1.6% 1/61 • 3 years 6 months	0.00% 0/60 • 3 years 6 months
Blood and lymphatic system disorders Leukocytosis	19.7% 12/61 • 3 years 6 months	18.3% 11/60 • 3 years 6 months
Blood and lymphatic system disorders Thrombocytopenia	19.7% 12/61 • 3 years 6 months	6.7% 4/60 • 3 years 6 months
Hepatobiliary disorders Abnormal liver function test	0.00% 0/61 • 3 years 6 months	1.7% 1/60 • 3 years 6 months
Hepatobiliary disorders conjugated hyperbilirubinemia	23.0% 14/61 • 3 years 6 months	13.3% 8/60 • 3 years 6 months
Renal and urinary disorders Elevated serum creatinine	1.6% 1/61 • 3 years 6 months	3.3% 2/60 • 3 years 6 months
Blood and lymphatic system disorders Anemia	26.2% 16/61 • 3 years 6 months	20.0% 12/60 • 3 years 6 months
Metabolism and nutrition disorders metabolic acidosis	29.5% 18/61 • 3 years 6 months	31.7% 19/60 • 3 years 6 months
Metabolism and nutrition disorders Metabolic alkalosis	9.8% 6/61 • 3 years 6 months	13.3% 8/60 • 3 years 6 months
Metabolism and nutrition disorders Elevated Blood Urea Nitrogen	45.9% 28/61 • 3 years 6 months	43.3% 26/60 • 3 years 6 months
Metabolism and nutrition disorders Hyperkalemia	34.4% 21/61 • 3 years 6 months	33.3% 20/60 • 3 years 6 months
Hepatobiliary disorders Hyperbilirubinemia	11.5% 7/61 • 3 years 6 months	15.0% 9/60 • 3 years 6 months
Metabolism and nutrition disorders Hypernatremia	13.1% 8/61 • 3 years 6 months	21.7% 13/60 • 3 years 6 months

Additional Information

Rose Marie Viscardi, M.D.

University of Maryland

Phone: 410-706-1913

Email: rviscard@som.umaryland.edu

Results disclosure agreements

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