Antibiotics for Neurodevelopmental Outcomes in Preterm Infants

(NANO-FU Trial)

Not yet recruiting at 14 trial locations

Overseen By Rebecca Dorner, MD

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Sharp HealthCare

Must not be taking: Antibiotics

Disqualifiers: Sepsis risk, Respiratory issues, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 48 hours

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether avoiding antibiotics immediately after birth can reduce behavioral and brain development issues in very preterm infants (born between 23 and 30 weeks of pregnancy). Researchers aim to determine if skipping early antibiotics leads to better development by age two. The trial compares two groups of newborns: one receiving antibiotics (ampicillin and gentamicin) and another receiving a placebo within the first 48 hours of life. It seeks infants born at very early stages of pregnancy who are neither at low nor high risk for early infections. As a Phase 3 trial, this study represents the final step before FDA approval, offering a chance to contribute to important research that could improve infant care.

Will I have to stop taking my current medications?

The trial information does not specify whether participants must stop taking their current medications. It focuses on withholding antibiotics at birth for newborns, so it may not directly affect other medications you are taking.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A previous study administered ampicillin to preterm infants to treat early-onset sepsis, a serious infection. The study found that two doses of 50 mg/kg each were effective and minimized side effects. However, ampicillin can sometimes delay clotting in newborns with cuts or bruises.

For gentamicin, research suggests that preterm infants require slightly higher doses than full-term infants for better bacterial control. One study showed that gentamicin reduced hospital stays and the duration of respiratory support needed. However, there is a risk of higher drug levels in the blood, which might cause side effects.

Both medicines are generally well-tolerated in preterm infants, but like any treatment, they may have side effects. These studies help doctors weigh the risks and benefits to ensure infant safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the use of antibiotics like Ampicillin and Gentamicin for preterm infants because these treatments aim to improve neurodevelopmental outcomes by preventing early infections. Unlike standard treatments that may not address the immediate bacterial threats faced by very preterm infants, these antibiotics are administered within the crucial first 48 hours of life. This early intervention could potentially protect the delicate developing brain from infection-related damage, offering a proactive approach that standard care might not provide.

What evidence suggests that this trial's treatments could be effective for neurodevelopmental outcomes in preterm infants?

Research has shown that using the antibiotics ampicillin and gentamicin together effectively treats infections in newborns, including those born prematurely. Studies indicate that this antibiotic pair usually works well against bacteria causing blood infections (sepsis) in these babies. Newborns have generally tolerated this treatment well in the past. However, the success of different antibiotic treatments for young infants with sepsis has varied, and no single treatment is clearly superior. In this trial, some very preterm infants will receive empiric antibiotic treatment with ampicillin and gentamicin in the first 48 hours of life, while others will receive a placebo. The trial aims to determine if withholding antibiotics immediately after birth affects the baby's long-term brain development. ^{6 7 8 9 10}

Who Is on the Research Team?

Anup Katheria, MD

Principal Investigator

Sharp HealthCare

Are You a Good Fit for This Trial?

The NANO follow-up study is for families enrolled in the original NANO trial, which involves premature infants. It's not for low-risk infants or those with conditions like high risk of sepsis, respiratory issues requiring significant support, hemodynamic instability, major congenital anomalies, or prior antibiotic use.

Inclusion Criteria

Families that have agreed to participate and are enrolled in the parent NANO trial will be eligible for the NANO follow-up study. There will be no exclusions for eligible children entering the follow-up study.

My newborn was born between 23.0-30.6 weeks of gestation at a study site.

Exclusion Criteria

My infant needs a ventilator to breathe and requires a high level of oxygen.

Major congenital anomalies

My infant is at low risk for early onset sepsis.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Neonates receive either empiric antibiotic treatment or placebo within the first 48 hours of life

48 hours

Follow-up

Participants are monitored for neurodevelopmental and behavioral outcomes at 1 and 2 years of age

24 months

1 virtual visit at 1 year, 1 in-person visit at 2 years

Exploratory Analysis

Evaluation of interactions among genetics, environment, and microbiota with antibiotic exposure and long-term outcomes

What Are the Treatments Tested in This Trial?

Interventions

• Ampicillin
• Gentamicin
• Placebo

Trial Overview This study tests whether withholding antibiotics from premature babies at birth can reduce neurodevelopmental disorders by age two. It compares outcomes between babies given Gentamicin and Ampicillin versus a placebo while considering genetic factors and gut bacteria.

How Is the Trial Designed?

Group I: Very preterm infants that receive empiric antibiotic treatment in the first 48 hours of life Active Control 2 Interventions

Neonates in this group will have been enrolled and randomized into the NANO trial and received a blinded 48 hour course of empiric antibiotic treatment.

Group II: Very preterm infants that do not receive empiric antibiotic treatment in the first 48 hours of life Placebo Group 1 Intervention

Neonates in this group will have been enrolled and randomized into the NANO trial and received a blinded 48 hour course of placebo.

Ampicillin is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Ampicillin for:

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Skin and soft tissue infections
• Gastrointestinal infections

Approved in European Union as Ampicillin for:

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Skin and soft tissue infections
• Gastrointestinal infections

Approved in Canada as Ampicillin for:

• Bacterial infections
• Urinary tract infections
• Respiratory tract infections
• Skin and soft tissue infections
• Gastrointestinal infections

Who Is Running the Clinical Trial?

Sharp HealthCare

Lead Sponsor

Trials

42

Recruited

17,600+

University of Pittsburgh

Collaborator

Trials

1,820

Recruited

16,360,000+

Morgan Stanley Children's Hospital

Collaborator

Trials

10

Recruited

5,012,000+

University of Louisville

Collaborator

Trials

353

Recruited

76,400+

Sharp Mary Birch Hospital for Women & Newborns

Collaborator

Trials

13

Recruited

6,600+

Children's Hospital of Philadelphia

Collaborator

Trials

749

Recruited

11,400,000+

Jefferson Medical College of Thomas Jefferson University

Collaborator

Trials

13

Recruited

13,900+

University of South Florida

Collaborator

Trials

433

Recruited

198,000+

Westchester Medical Center

Collaborator

Trials

9

Recruited

6,500+

Yale University

Collaborator

Trials

1,963

Recruited

3,046,000+

Published Research Related to This Trial

In a study of 1162 critically ill neonates on mechanical ventilation, those treated with ampicillin plus cefotaxime had worse outcomes compared to those receiving ampicillin plus gentamicin, including higher rates of late-onset sepsis and in-hospital mortality.

The use of ampicillin plus cefotaxime did not improve outcomes for neonates with early-onset sepsis and was linked to longer hospital stays, suggesting it should not be routinely used as empiric treatment in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influences of Initial Empiric Antibiotics with Ampicillin plus Cefotaxime on the Outcomes of Neonates with Respiratory Failure: A Propensity Score Matched Analysis. Ou-Yang, MC., Hsu, JF., Chu, SM., et al.[2023]

The combination of sulbactam and ampicillin was safely administered to 16 newborn infants, achieving satisfactory plasma concentrations with a dosage of 50 mg/kg every 12 hours, indicating it could be effective for treating infections in this population.

The pharmacokinetics showed longer elimination half-lives for both drugs in newborns compared to adults, but there was no evidence of drug accumulation, suggesting that the regimen is well tolerated and appropriate for further clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. Sutton, AM., Turner, TL., Cockburn, F., et al.[2019]

In a study of 192 neonates, 43% exhibited elevated gentamicin levels, indicating a significant risk of potential toxicity, especially in preterm infants.

Preterm neonates, particularly those weighing less than 2.5 kg, showed a higher incidence of elevated gentamicin levels (61%), suggesting that dosage adjustments may be necessary to reduce toxicity in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gentamicin use in neonates: should we have a change of practice? Krishnamoorthy, SS., Nair, A., Furness, J., et al.[2013]

Sulbactame, a beta-lactamase inhibitor, demonstrated low toxicity with a lethal dose (DL50) in mice exceeding 4,000 mg/kg, indicating a strong safety profile when used alone or in combination with ampicillin or amoxicillin.

The combination of sulbactame with ampicillin or amoxicillin showed effective serum levels against tested bacteria, suggesting its therapeutic potential in treating infections caused by beta-lactamase producing germs, comparable to the established product Unasyn.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological studies of sulbactam and its association with semisynthetic beta-lactam antibiotics]. Nechifor, M., Buiuc, D., Diaconu, E., et al.[2013]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC3763620/

Ampicillin and Gentamicin Are a Useful First-line ... Ampicillin and gentamicin are usually effective against all the bacterial agents causing community-acquired sepsis in neonates as this combination has ...

2. withpower.com withpower.com/trial/phase-3-premature-birth-3-2024-b646f

Antibiotics for Neurodevelopmental Outcomes in Preterm ... The combination of ampicillin and gentamicin has been used effectively in treating infections in newborns, as seen in studies where it was well tolerated and ...

3. publications.aap.org publications.aap.org/pediatrics/article/154/Supplement%201/e2024066588F/198465/Efficacy-of-Antibiotic-Regimens-for-Sepsis-or

Efficacy of Antibiotic Regimens for Sepsis or Possible ... We found limited evidence to support any single antibiotic regimen as superior to alternate regimens to treat young infant sepsis or PSBI.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9495226/

Use of Antibiotics in Preterm Newborns - PMC - PubMed Central A retrospective evaluation of previously published popPK models has been performed for both ampicillin and gentamicin on preterm neonates with GA <28 weeks [130] ...

5. researchgate.net researchgate.net/publication/260217510_Early_Empiric_Antibiotic_Use_in_Preterm_Infants_Is_Associated_with_Lower_Bacterial_Diversity_and_Higher_Relative_Abundance_of_Enterobacter

Early Empiric Antibiotic Use in Preterm Infants Is ... The duration of treatment with ampicillin plus gentamicin positively correlated with the decrease in alpha diversity (58) . One study found a ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC9262754/

Ampicillin Dosing in Premature Infants for Early-onset Sepsis For EOS in preterm infants, two ampicillin doses (50mg/kg) provided optimal bactericidal exposures, while minimizing potential toxicity.

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10046592/

Developmental Pharmacokinetics of Antibiotics Used in ... The objective of this review is to summarize the evidence about the developmental changes (specific for preterm and full-term infants, separately) of ...

8. publications.aap.org publications.aap.org/pediatriccare/drug-monograph/18/5199/Ampicillin-and-Sulbactam

Ampicillin and Sulbactam | Drug Lookup | Pediatric Care ... Based on available data, penicillin antibiotics are generally considered compatible for use during pregnancy (Ailes 2016; Bookstaver 2015; Crider 2009; Damkier ...

9. academic.oup.com academic.oup.com/jac/article/74/11/3150/5522501

Oral antibiotics for neonatal infections: a systematic review ... Oral antibiotics administered to neonates are absorbed and result in adequate serum levels, judged by MICs of relevant pathogens, over time.

10. jpp.mums.ac.ir jpp.mums.ac.ir/article_9526_48a7504df2eaaf16c733b73cdb52c086.pdf

Clinical Pharmacology of Ampicillin in Neonates and Infants Ampicillin can prolong the bleeding times of term and late preterm neonates, but its effect on very-low-birth- weight neonates, who already have ...