Vitality in Infants Via Azithromycin for Neonates Trial (VIVANT)

Nearly half of child deaths occur during the neonatal period, and 80% of those occur in babies with low birthweight. Although tremendous progress has been made towards reducing under-five mortality globally, declines in neonatal mortality lag behind those observed in older children. Low birthweight babies are at increased risk of poor outcomes compared to those who are term-appropriate for gestational age, including mortality, stunting, and growth failure. Recent evidence has demonstrated that the incidence of wasting and linear growth failure is highest between birth and 3 months of age, substantially earlier than previously thought. Interventions are urgently needed to improve outcomes in low birthweight babies; however, these interventions must not interfere with breastfeeding and thus some well-established interventions used to treat or prevent malnutrition in older children cannot be considered. The investigators recently demonstrated that biannual mass azithromycin distribution reduces all-cause childhood mortality by approximately 25% in infants aged 1-5 months, with stronger effects seen in underweight infants. This study did not include neonates due to the risk of infantile hypertrophic pyloric stenosis (IHPS) that has been hypothesized to be associated with macrolide use during early infancy. However, our study team documented only a single case of IHPS among 21,833 neonates enrolled in a trial of azithromycin versus placebo administered to neonates aged 8-27 days for prevention of infant mortality, documenting no major risk of IHPS associated with azithromycin. Here, the investigators propose an individually randomized trial where participants will receive a single oral dose of azithromycin (administered either during the neontal period or 21 days after enrollment), two does of oral azithromycin spaced 21 days apart, or two doses of placebo to evalute if azithromycin improves nutritional outcome and reduces infectious burden among neonates aged 1-27 days who are either low birthweight (<2500 g at birth) or underweight (weight-for-age Z-score < -2 at enrollment). The primary outcome will be weight-for-age Z-score at 6 months of age compared between arms. The investigators anticipate that the results of this study will provide definitive evidence on azithromycin as an early intervention for low birthweight/underweight neonates, who are at the highest risk of adverse outcomes.

Study Overview

• Status: Not yet recruiting
• Conditions: Infectious Disease; Nutritional Deficiency; Neonatal Death
• Intervention / Treatment: Drug: Azithromycin at Baseline; Drug: Azithromycin at Day 21; Other: Placebo at Day 21; Other: Placebo at Baseline

Detailed Description

The Vitality in Infants Via Azithromycin for Neonates Trial (VIVANT) is a proposed 1:1:1:1 randomized placebo-controlled trial to determine whether a single oral dose of azithromycin (20 mg/kg) administered either in the early or late neonatal/early infancy period is effective for improving infant growth outcomes, and if there is additional benefit of administration of a second dose of azithromycin 21 days after the first dose (Figure 2). This intervention schedule will allow for several questions related to azithromycin administration in neonates to be answered efficiently, including:

1. A single oral azithromycin dose compared to placebo, administered either earlier or later during the neonatal period or early infancy.
2. Two oral doses of azithromycin spaced 21 days apart compared to placebo.
3. Two oral doses of azithromycin compared to a single oral dose of azithromycin, which would allow for determination of any dose-dependent effects.
4. An early dose of azithromycin compared to a later dose of azithromycin, which may be beneficial if administration of azithromycin earlier during the neonatal period increases risk of IHPS

• Study Type: Interventional
• Enrollment (Estimated): 5000
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Elodie Lebas, RN; Phone Number: (415) 476-1442; Email: elodie.lebas@ucsf.edu
• Study Contact Backup: Name: Catherine Oldenburg, ScD; Phone Number: (415) 476-1442; Email: catherine.oldenburg@ucsf.edu

Study Locations

• Burkina Faso
  • Nouna, Burkina Faso, BP02
    • Centre de recherche en Santé de nouna
    • Contact: Ali Sie, PhD; Email: sieali@yahoo.fr
    • Contact: Mamadou Bountogo, MD; Email: drbountogo@yahoo.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 day to 3 weeks (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Aged 1-27 days old
• Birthweight < 2500 g and/or weight-for-height Z score <- 2 standard deviations at enrollment
• Weigh at least <1500 g at time of enrollment
• Able to feed orally
• Family intends to stay in the study area for at least 6 months
• Appropriate consent from at least one caregiver
• No known allergy to macrolides
• No hepatic failure manifested by neonatal jaundice
• Not currently an inpatient at the clinic
• Not being transferred to a hospital for clinical complications

Exclusion Criteria:

• Birthweight > 2500 g
• Weigh less than 1500 g at time of enrollment
• Unable to feed orally
• Family planning to move within 6 months
• Mother/ caregiver not willing to participate
• Allergic to macrolides
• Hepatic failure manifested by neonatal jaundice
• Currently being seen as an inpatient at the clinic
• Currently being transferred to a hospital for clinical complications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Azithro-Azithro; A single oral dose of azithromycin (20 mg/kg) at baseline and a single oral dose of azithromycin (20 mg/kg) at the day 21 follow-up	Drug: Azithromycin at Baseline; this group will be randomized to receive a single oral dose of azithromycin (20mg/kg) at baseline; Drug: Azithromycin at Day 21; this group will be randomized to receive a single oral dose of azithromycin (20mg/kg) at the day 21 visit
Active Comparator: Azithro-Placebo; A single oral dose of azithromycin (20 mg/kg) at baseline and a single oral dose of matching placebo at the day 21 follow-up	Drug: Azithromycin at Baseline; this group will be randomized to receive a single oral dose of azithromycin (20mg/kg) at baseline; Other: Placebo at Day 21; This group will be randomized to receive Placebo at the day 21 visit
Active Comparator: Placebo-Azithro; A single oral dose of placebo at baseline and a single oral dose of azithromycin (20 mg/kg) at the day 21 follow-up	Drug: Azithromycin at Day 21; this group will be randomized to receive a single oral dose of azithromycin (20mg/kg) at the day 21 visit; Other: Placebo at Baseline; this group will be randomized to receive Placebo at baseline
Placebo Comparator: Placebo-Placebo; A single oral dose of placebo at baseline and a single oral dose of matching placebo at the day 21 follow-up	Other: Placebo at Day 21; This group will be randomized to receive Placebo at the day 21 visit; Other: Placebo at Baseline; this group will be randomized to receive Placebo at baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
weight gain at 6 month of age	Weight for Age Z score	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IHPS	Signs of IHPS will be screened at the 21 day follow up visit. diagnosed cases of IHPS will be reported by arm	21 days
Mortality at 6 months	Vital status will be verified at each follow up visit	6 months

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: Centre de Recherche en Sante de Nouna, Burkina Faso
• Investigators: Principal Investigator: Catherine Oldenburg, ScD, University of California, San Francisco

Study record dates

Study Major Dates

• Study Start (Estimated): July 31, 2024
• Primary Completion (Estimated): July 31, 2027
• Study Completion (Estimated): July 31, 2027

Study Registration Dates

• First Submitted: February 24, 2023
• First Submitted That Met QC Criteria: February 28, 2023
• First Posted (Actual): March 10, 2023

Study Record Updates

• Last Update Posted (Estimated): December 4, 2023
• Last Update Submitted That Met QC Criteria: November 30, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Low birth weight; underweight neonates
• Additional Relevant MeSH Terms: Pathologic Processes; Disease Attributes; Nutrition Disorders; Pregnancy Complications; Death; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Infections; Communicable Diseases; Malnutrition; Perinatal Death; Anti-Infective Agents; Anti-Bacterial Agents; Azithromycin
• Other Study ID Numbers: 21-34232

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes