Caffeine Citrate in Preterm Infants at Risk of Apnea in Zambia

Randomized Controlled Trial of Caffeine Citrate in Preterm Infants at Risk of Apnea in Zambia

The goal of this clinical trial is to learn if caffeine citrate prevents apneic events that result in sick visits in moderately preterm infants after discharge from the hospital. It will also learn if the use of caffeine leads to better developmental outcomes at 12 months of age.

Our research questions are:

1. Does continued treatment of moderately preterm newborns with caffeine citrate after hospital discharge prevent or decrease apneic events that result in sick visits?
2. Will the continued use of caffeine citrate lead to improved developmental outcomes among infants at 12 months of age?

Researchers will compare caffeine citrate to a placebo (a look-alike substance that contains no drug) to see if caffeine citrate prevents apneic spells which result in healthcare visits.

Parents of participants will:

1. Administer caffeine citrate 20mg/kg/day or a placebo (equivalent volume of sterile water) orally every day for up to 28 days after hospital discharge
2. Keep a diary of symptoms and any apneic events
3. Check in with researchers via telephone call once a week
4. Return to clinic for infant physical examination at 28 days
5. Return to the clinic for infant physical examination at 2 months

5. Return to clinic for infant neurodevelopmental examination with Ages and Stages Questionnaire at 12 months of age

Study Overview

• Status: Recruiting
• Conditions: Apnea of Prematurity; Development, Infant; Premature Infant Disease
• Intervention / Treatment: Drug: Caffeine citrate 20mg/kg/day; Drug: Placebo-Sterile water 1ml/kg/day

Detailed Description

Once an infant has been deemed stable by the neonatologist and the neonatologist recommends discontinuing treatment for apnea of prematurity 5 days before hospital discharge as per standard of care, the parent/guardian will be approached for consent. Following consent, study participants will be randomized to either the Intervention Arm (20mg/kg/day caffeine citrate; 2mg/ml) dose and equal volume of placebo (sterile water) using trial-specific single dose caffeine/placebo vials. Upon the study participant's hospital discharge, the pharmacist will prepare the caffeine citrate and placebo relevant to the weight of the infant within 48 hours prior to discharge. The doses will not be adjusted for weight gain after discharge. Caffeine levels will not be checked routinely and checking levels will be discouraged to optimize masking.

While at the hospital, infants will receive the oral dose from government staff. Following hospital discharge, the parent/guardian will be given enough doses of caffeine or equivalent placebo for 28 days and will be asked to administer it to their infant orally daily, at the same time, until day 28. Unlike the intervention arm, all study participants randomized to the control arm (placebo) will discontinue receiving caffeine and will begin receiving placebo (sterile water) in the same volume orally as those in the intervention arm. The parent/guardian will also be given a booklet to register any apneic spells. The study RA will contact the parent/guardian on a weekly basis, up to day 28 and once at 2 months after hospital discharge for patient clinical monitoring and follow-up purposes.

Upon completion of the study at 12 months of life, all study participants will return to the hospital for neurodevelopmental screening using the Ages and Stages-3 Questionnaire for 12 months.

Data will be collected onto paper forms, which will then be entered into a REDCap Database, housed at the Centre for Infectious Disease Research in Zambia (CIDRZ) offices. Data forms will be kept in locked cabinets, retained and destroyed per incineration after 5 years. Access to the data forms and REDCap Database will be restricted to those with a need to know.

• Study Type: Interventional
• Enrollment (Estimated): 340
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Albert Manasyan, MD; Phone Number: +260 976 448 994; Email: Albert.Manasyan@cidrz.org
• Study Contact Backup: Name: Waldemar A Carlo, MD; Phone Number: 2059344680; Email: wacarlo@uabmc.edu

Study Locations

• Zambia
  • Lusaka Province
    • Lusaka, Lusaka Province, Zambia, 10100
      • Recruiting
      • University Teaching Hospital
      • Contact: Albert Manasyan, MD; Phone Number: +260 976 448 994; Email: Albert.Manasyan@cidrz.org
      • Contact: Waldemar A Carlo, MD; Phone Number: 2059344680; Email: wacarlo@uabmc.edu
      • Principal Investigator: Jyoti Lakhwani, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Newborns:

1. 29 0/7 to 33 6/7 weeks GA (or with a birth weight 1.0 to 2.0 kg if pregnancy dating is unreliable) admitted to the UTH NICU,
2. On methylxanthines with plans to discontinue on methylxanthine,
3. Off oxygen therapy for >48 hours at the time of evaluation for eligibility,
4. Receiving full daily feeds,
5. Deemed stable and ready to go off caffeine as recommended by the Neonatologist
6. 18+ years of age (parent)

Exclusion Criteria:

1. Newborns with neuromuscular conditions affecting respiration,
2. Major congenital malformations and genetic disorders,
3. Unable to obtain parental or guardian consent

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Caffeine Citrate 20mg/kg/day; Caffeine Citrate 20 mg/kg/day given orally once a day for 28 days. (2mg/ml)	Drug: Caffeine citrate 20mg/kg/day; Caffeine citrate 20mg/kg/day given orally once daily for 28 days
Placebo Comparator: Placebo; Sterile water 1ml/kg/day given orally once a day for 28 days.	Drug: Placebo-Sterile water 1ml/kg/day; Placebo-sterile water 1mg/kg/day given orally once daily for 28 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of apneic events	Documentation or report of apnea of prematurity [AoP], a condition exhibited by cessation of breathing for ≥20 or <20 seconds accompanied by bradycardia and/or cyanosis	28 days after discharge
Number of visits to healthcare professionals related to apneic events	Documentation or report of sick visit	28 days after discharge

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of all-cause sick visits	Documentation or report of sick visit	2 months after discharge
Percentage of neonatal mortality within 2 months after discharge	Documentation of neonatal death	2 months after discharge
Infant/Child Developmental Assessment	Score on "Ages and Stages Questionnaire" obtained at clinic visit	12 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Centre for Infectious Disease Research in Zambia; University Teaching Hospital, Lusaka, Zambia

Study record dates

Study Major Dates

• Study Start (Actual): June 17, 2026
• Primary Completion (Estimated): May 31, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: July 18, 2024
• First Submitted That Met QC Criteria: July 18, 2024
• First Posted (Actual): July 24, 2024

Study Record Updates

• Last Update Posted (Actual): June 23, 2026
• Last Update Submitted That Met QC Criteria: June 18, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Pathological Conditions, Signs and Symptoms; Signs and Symptoms; Apnea; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Neurotransmitter Agents; Purinergic Antagonists; Purinergic Agents; Central Nervous System Stimulants; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; caffeine citrate
• Other Study ID Numbers: UAB-300013205; UAB Dixon End Chair/3102800 (Other Identifier: University of Alabama at Birmingham); 000533428-0004 (Other Identifier: INSIGHT)

Drug and device information, study documents

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