Antibiotics for Neurodevelopmental Outcomes in Preterm Infants

(NANO-FU Trial)

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

802 Participants Needed

Trial Summary

What is the purpose of this trial?

The NANO follow-up study is designed to determine whether a simple, cost-effective intervention- withholding antibiotics at birth- reduces clinically relevant outcomes such as behavioral and neurological impairment at 2 years of age. This study will be the largest study evaluating the effects of early antibiotics in children with comprehensive measures of neurodevelopment linked to genomic variants and microbiota interactions.

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.

What evidence supports the effectiveness of the drug combination of ampicillin and gentamicin for neurodevelopmental outcomes in preterm infants?

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 did not lead to significant hearing loss or developmental issues. However, its effectiveness specifically for neurodevelopmental outcomes in preterm infants is not directly supported by the provided research. ^{1 2 3 4 5}

Is the combination of antibiotics used in the trial generally safe for humans?

The combination of sulbactam and ampicillin has been shown to be well tolerated in newborns, including preterm infants, with no significant evidence of drug accumulation. However, using ampicillin with cefotaxime in critically ill neonates was associated with worse outcomes, including a higher risk of infections from resistant bacteria. ^{1 2 4 6 7}

How is the drug combination of Ampicillin and Gentamicin unique for preterm infants?

This drug combination is unique because it explores the potential impact on neurodevelopmental outcomes in preterm infants, a novel focus compared to its traditional use for treating infections. While both antibiotics are commonly used in neonates, this study specifically investigates their effects on brain development, which is not a standard treatment approach for this condition. ^{1 5 8 9 10}

Research Team

Anup Katheria, MD

Principal Investigator

Sharp HealthCare

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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 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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Recording of brainstem evoked potentials and their association with gentamicin in neonates. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetic study of sulbactam and ampicillin administered concomitantly by intraarterial or intravenous infusion in the newborn. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

A controlled study of intrathecal antibiotic therapy in gram-negative enteric meningitis of infancy. Report of the neonatal meningitis cooperative study group. [2019]

4. Switzerland 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. [2023]

5. United States pubmed.ncbi.nlm.nih.gov

Ototoxicity in neonates treated with gentamicin and kanamycin: results of a four-year controlled follow-up study. [2007]

6. Romania pubmed.ncbi.nlm.nih.gov

[Pharmacological studies of sulbactam and its association with semisynthetic beta-lactam antibiotics]. [2013]

7. England pubmed.ncbi.nlm.nih.gov

Switch therapy in full-term neonates with presumed or proven bacterial infection. [2023]

8. Germany pubmed.ncbi.nlm.nih.gov

The possible preterm birth preventive effect of ampicillin during pregnancy. [2013]

9. Hungary pubmed.ncbi.nlm.nih.gov

[The possible effect of ampicillin treatment in preventing preterm birth]. [2013]

10. Scotland pubmed.ncbi.nlm.nih.gov

Gentamicin use in neonates: should we have a change of practice? [2013]