Target Weaning Oxygen to Determine Cafffeine Duration for AOP (DCAP)

Target Weaning Oxygen to Determine Duration of Caffeine for Apnea of Prematurity: a Multicenter, Prospective, Randomized Controlled Trial

Caffeine, a typical representative of methylxanthine, is world-widely used to manage apnea of prematurity (AOP) in neonatology. However, an appropriate medication regimen of caffeine has not been well defined until now. For example, in terms of the duration of caffeine, AAP guideline for AOP (2016) and British NICE guideline for neonatal respiratory care (2019) all recommended discontinuing caffeine when the infants reached a postmenstrual age (PMA) ≥33weeks and had a stable respiratory status, commonly manifested by weaning from non-invasive ventilation and free of apneic episodes for at least five consecutive days. Interestingly, the actual clinical settings seem to be not strictly following this recommendation. A survey of the neonatologist in North America revealed that a substantial variability existed among sites in the timing of caffeine discontinuation before discharge and the respiratory support at the time of caffeine discontinuation [1]. Another survey in Saudi Arabia also had a similar finding [2]. The optimal timing of discontinuing caffeine is still a conundrum in the field of neonatology.

Ideally, the optimal timing of discontinuing caffeine should be individual-specific. Published work has indicated that AOP and intermittent hypoxemia (IH) were frequently observed beyond 36 weeks' PMA in all gestational age groups, particularly in the 24- to 27-week infants [3, 4]. In the clinical settings, intermittent hypoxic and AOP episodes is a predominant cause of oxygen supplement in premature infants and commonly prolong the hospital stay. Optimizing arterial saturation by oxygen supplement is essential to achieve a stable cardiorespiratory status because hypoxemia could induce hypoxic sensitivity of the carotid bodies in neonates, resulting in more pronounced ventilatory depression and more frequent apneic episodes. Some RCTs have shown that continuing caffeine administration beyond PMA 34 weeks could reduce the frequency of IH episodes in premature infants [4, 5]. Therefore, theoretically, a prolonged caffeine administration over the usual duration could shorten the duration of oxygen supplements in those infants at high risk of frequent late AOP or IH. Target weaning oxygen could be an opportunistic indicator of discontinuing caffeine.

In light of the above considerations, a multicenter, retrospective, partially blinded, controlled trials will be conducted to verify the hypothesis that a novel caffeine regimen that weaning oxygen as the indicator of discontinuing caffeine could improve respiratory outcomes of very premature infants.

Study Overview

• Status: Completed
• Conditions: Apnea of Prematurity; Caffeine; Weaning Oxygen; Medicine Regimen
• Intervention / Treatment: Drug: Caffeine Citrate 20 MG/1 ML Intravenous Solution [CAFCIT]

• Study Type: Interventional
• Enrollment (Actual): 310
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Jianhui Wang; Phone Number: +86-13678428167; Email: wangjh@cqmu.edu.cn
• Study Contact Backup: Name: Yuan Shi; Phone Number: +86-(023)63635567; Email: shiyuan@hospital.cqmu.edu.cn

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China
      • The First Affiliated Hospital of USTC（University of Science and Technology of China）
  • Beijing
    • Beijing, Beijing, China
      • Peking Union Medical College Hospital
  • Chongqing
    • Chongqing, Chongqing, China, 400014
      • Yuan Shi
    • Chongqing, Chongqing, China
      • First Affiliated Hospital of Army Military Medical University
    • Dazu, Chongqing, China
      • The People's Hospital of Dazu
    • Fuling, Chongqing, China
      • Fuling Central Hospital of Chongqing City
    • Wanzhou, Chongqing, China
      • Chongqing University Three Gorges Hospital
    • Wanzhou, Chongqing, China
      • Chongqing Wanzhou Health Center for Women And Children
  • Fujian
    • Fuzhou, Fujian, China
      • Fuzhou Children's Hospital of Fujian Medical University
    • Xiamen, Fujian, China
      • Xiamen Children's Hospital
  • Gansu
    • Lanzhou, Gansu, China
      • Lanzhou university second hospital
  • Guangdong
    • Dongguan, Guangdong, China
      • Dongguan City Maternal&Child Health Hospital
    • Yunfu, Guangdong, China
      • Maternal and Child Health Hospital of Yunfu
    • Zhanjiang, Guangdong, China
      • Affiliated Hospital of Guangdong Medical University
    • Zhongshan, Guangdong, China
      • Boai Hospital of Zhongshan
  • Hainan
    • Haikou, Hainan, China
      • Haikou Hospital of the Maternal and Child Health
  • Henan
    • Zhengzhou, Henan, China
      • The Second Affiliated Hospital of Zhengzhou University
    • Zhengzhou, Henan, China
      • The Third Affiliated Hospital of Zhengzhou University
  • Hubei
    • Wuhan, Hubei, China
      • Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Hunan
    • Changsha, Hunan, China
      • Hunan Children's Hospital
    • Hengyang, Hunan, China
      • Hengyang Maternity and Child care hospital
  • Jiangsu
    • Nanjing, Jiangsu, China
      • Children's Hospital of Nanjing Medical University
    • Nanjing, Jiangsu, China
      • First Affiliation Hospital of Nanjing Medical University
  • Jiangxi
    • Nanchang, Jiangxi, China
      • The First Affiliated Hospital of Nanchang University
  • Jilin
    • Changchun, Jilin, China
      • The First Bethune Hospital of Jilin University
  • Shandong
    • Jinan, Shandong, China
      • Qilu Children's Hospital of ShanDong University
    • Linyi, Shandong, China
      • Women & Children's Health Care Hospital of Linyi
  • Shanghai
    • Shanghai, Shanghai, China
      • Shanghai Children's Medical Center
  • Shanxi
    • Xi'an, Shanxi, China
      • The First Affiliated Hospital of Xi'an Jiaotong University
  • Sichuan
    • Guangyuan, Sichuan, China
      • Guangyuan Central Hospital
    • Leshan, Sichuan, China
      • People's Hospital Of Leshan
    • Luzhou, Sichuan, China
      • Hospital T. C. M Affiliated to Southwest Medical University
    • Mianyang, Sichuan, China
      • Mianyang Central Hospital
    • Panzhihua, Sichuan, China
      • Panzhihua Central Hospital
    • Yibin, Sichuan, China
      • The Second People's Hospital of Yibin
  • Yunnan
    • Kunming, Yunnan, China
      • The Second Affiliated Hospital of Kunming Medical University
    • Kunming, Yunnan, China
      • Kunming Children's hospital
    • Qujing, Yunnan, China
      • Qujing City Maternal and Child Health Hospital
    • Wenshan, Yunnan, China
      • The People's Hosiptal of Wenshan Prefecture
    • Zhaotong, Yunnan, China
      • The First People's Hospital of Zhaotong
  • Zhejiang
    • Ningbo, Zhejiang, China
      • Ningbo Women & Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 weeks to 6 months (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• premature infants with gestational age <30 weeks
• postmenstral age ≥32weeks
• a history of caffeine therapy
• no current positive pressure respiratory support, and free of apnea for at least five consecutive days, but still oxygen dependent
• parents or legal guardians sign informed consent to attend this study

Exclusion Criteria:

• congenital cardiorespiratory malformation, or chromosomal abnormalities
• Grade III/IV intraventricular hemorrhage, or probable brain injury attributable to confirmed central nervous system infection, severe periventricular leukomalacia or other entities;
• underwent tracheostomy
• currently on sedatives, opioids, or other medication related to depressed breath

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ongoing caffeine with oxygen supplement (group 1); samples assigned to the "ongoing caffeine with oxygen supplement (group 1)" will continue caffeine administration combining with oxygen supplement until the patients are weaned from oxygen.	Drug: Caffeine Citrate 20 MG/1 ML Intravenous Solution [CAFCIT]; after randomization, caffeine citrate will be contineously prescribed to those patients assigned to the "ongoing caffeine with oxygen supplement (group 2) with a medication regimen of 10mg/kg.dose, once daily, and weekly adjustment based on the working weight.
Active Comparator: discontinuing caffeine with oxygen supplement (group 2); samples assigned to the "discontinuing caffeine with oxygen supplement (group 2)" will discontinue caffeine immediately after randomization, while oxygen supplement is going on.	Drug: Caffeine Citrate 20 MG/1 ML Intravenous Solution [CAFCIT]; after randomization, caffeine citrate will be contineously prescribed to those patients assigned to the "ongoing caffeine with oxygen supplement (group 2) with a medication regimen of 10mg/kg.dose, once daily, and weekly adjustment based on the working weight.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
recurrence of apnea of prematurity (RAP)	Either of the following condition is defined as a RAP event: 1. heart rate <100 beats/min; 2. weak respiratory effort requiring mask-bag ventilation; 3. A high-flow nasal cannula (HFNC) and various noninvasive and invasive ventilation are dictated by the clinical condition, where HFNC is defined as the oxygen flow is ≥2L/min; 4. Restarted caffeine therapy is considered at the discretion of the healthcare team.	from date of randomization until the date of discharge, assessed up to 100 days of life
duration of oxygen supplement after randomization	duration of oxygen supplement after randomization	from date of randomization until the date of discharge, assessed up to 100 days of life
duration of hospital stay after randomization	duration of hospital stay after randomization	from date of randomization until the date of discharge, assessed up to 100 days of life

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
postmenstrual age of discharging home	postmenstrual age at which the infants are discharged home	from date of randomization until the date of discharge, assessed up to 100 days of life
onset of bronchopulmonary dysplasia	onset of bronchopulmonary dysplasia, defined by oxygen dependence at the postmenstrual age of 36 weeks.	from date of randomization until the date of discharge, assessed up to 100 days of life
severity of bronchopulmonary dysplasia	evaluate the severity of bronchopulmonary dysplasia according to the 2016 NICHD proposed revision	from date of randomization until the date of discharge, assessed up to 100 days of life
restart caffine therapy	either of the following condition considers restarting caffeine therapy: 1. RAP event requires additional interventions to positioning, suction, and tactile stimulation; 2. intermittent hypoxemia ≥ 5 episodes per day where intermittent hypoxemia is referred to as a transient desaturation with Saturation <90%, but without bradycardia; 3. restart caffeine therapy at the discretion of the healthcare team.	from date of randomization until the date of discharge, assessed up to 100 days of life
restart noninvasive ventilation	either of the following conditions considers restarting non-invasive ventilation: 1.patients exhibit severe respiratory distress, including but not limited to tachypnea, chest indrawing, and grunting; 2. In the setting of nasal cannula oxygen supplemental, PaO2<50mmHg or SpO2<90% at the effective FiO2≥30%； 3. In the setting of incubator oxygen or hood oxygen supplement, PaO2<50mmHg or SpO2<90% at effective FiO2≥30% at the measured FiO2≥30%；4. Restart non-invasive ventilation at the discretion of the healthcare team.	from date of randomization until the date of discharge, assessed up to 100 days of life
reintubating the patients	Either of the following conditions considers reintubating the patients: 1. Severe respiratory acidosis with PaCO2>65 mmHg and pH<7.2; 2. Refractory hypoxemia at maximal setting in the non-invasive ventilation ( SpO2< 90%, with FiO2=0.4，and PEEP reaching eight cmH2O in CPAP/NIPPV，or Paw reaching 16 cmH2O in NHFOV; 3. Severe pulmonary hemorrhage; 4. Frequent apneic episodes (≥3 episodes per hour), or at least one episode within the last 24hours requiring mask-bag ventilation, which does not respond well to methylxanthine; 5. Hemodynamic instability after a recent occurrence of neonatal resuscitation; 6. Reintubating the patients at the discretion of the healthcare team.	from date of randomization until the date of discharge, assessed up to 100 days of life
hospitalization cost after randomization	hospitalization cost after randomization, which includes medicine cost (caffeine, and other medicine, respectively), and other healthcare cost	from date of randomization until the date of discharge, assessed up to 100 days of life

Collaborators and Investigators

• Sponsor: Children's Hospital of Chongqing Medical University
• Investigators: Study Director: Yuan Shi, Children's Hospital of Chongqing Medical University

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2021
• Primary Completion (Actual): October 15, 2023
• Study Completion (Actual): October 15, 2023

Study Registration Dates

• First Submitted: March 30, 2021
• First Submitted That Met QC Criteria: April 27, 2021
• First Posted (Actual): May 3, 2021

Study Record Updates

• Last Update Posted (Actual): October 18, 2023
• Last Update Submitted That Met QC Criteria: October 16, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: caffeine; apnea of prematurity; discontinuation
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Respiration Disorders; Signs and Symptoms, Respiratory; Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Apnea; Premature Birth; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Caffeine; Caffeine citrate
• Other Study ID Numbers: 20210326

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