CaffeinICU Study - A Pilot Study on the Feasibility and Safety of Oral Caffeine in ICU Patients With Coma

Encephalopathy Clinical Trial

— CaffeinICU  

Official title:

CaffeinICU Study - A Multi-centre Pilot Study to Examine the Safety and Feasibility of Oral Caffeine in Critically Ill Adult Patients With Low Glasgow Coma Scale Score.

Clinical Trial Details — Status: Suspended

Administrative data

• NCT number: NCT05232734
• Other study ID #: 2021/2556
• Status: Suspended
• Phase: Phase 2
• Start date: November 24, 2022
• Est. completion date: December 31, 2025

Study information

• Verified date: May 2024
• Source: Singapore General Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background: Depressed Glasgow Coma Scale (GCS) is common among critically ill patient s in the intensive care unit (ICU). It is one of the main reasons that hampers liberation from mechanical ventilation among ICU patients. Caffeine is commonly used in neonates for the treatment of apnea of prematurity. However, its efficacy has not been established in adult population. Objective: To find out the efficacy of oral caffeine in shortening duration of mechanical ventilation among adult patients. Hypothesis: Oral caffeine is effective as a central nervous system stimulant among adult patients with depressed GCS. Study design: Multi-center, randomised, double blind, placebo controlled clinical trial Population: Adult patients (≥ 21 years old) with GCS ≤ 8 from any causes (excluding surgically reversible causes) requiring continuation of mechanical ventilation, whom acute medical issues are stable or has resolved but not suitable for extubation solely due to depressed GCS, not planned for any surgical procedures within 24 hours and not on sedative agents for at least 24 hours, will be included in this study. For patients with primary Central Nervous System (CN lesions, neurologist or neurosurgeon approval will be obtained prior to recruitment. The exclusion criteria include known allergy or adverse reactions from caffeine, pregnant women, breast-feeding women, uncontrolled cardiac arrhythmias, uncontrolled hypertension, hyperactive delirium, patients with chronic kidney disease (CKD, any stage) who received midazolam or morphine infusion, patients who received barbiturate coma, patients who are on theophylline, aminophylline or psychotropic agents at the point of screening for recruitment, patients with feed intolerant, short bowel syndrome and active seizures. Intervention: Oral caffeine citrate 5mg/kg/dose twice a day (8am, 2pm) vs placebo Outcomes: Primary - Duration of mechanical ventilation Secondary - ICU mortality, 30-days mortality, ICU length of stay, blood pressure, heart rate, incidence of arrhythmia, GCS, incidence of re-intubation and need for tracheostomy

Description:

Depressed Glasgow Coma Scale (GCS) is common among critically ill patients in the intensive care unit (ICU). It is one of the main reasons that hampers liberation from mechanical ventilation among ICU patients. Current management of this disorder focuses mainly on supportive care and treatment of the underlying disease. Directed therapies targeting neurochemical and neurotransmitter pathways are not currently available and it represents an important area of research. Caffeine is commonly used in neonates for the treatment of apnea of prematurity. It is a CNS stimulant that stimulates central respiratory drive, increases medullary respiratory center sensitivity to carbon dioxide and improves diaphragmatic contractility. However, its efficacy has not been established in adult population. Objective: The primary objectives of the study are: 1. To study the safety of oral caffeine among critically ill adult patients. Specifically, we will observe for changes in the blood pressure and heart rate, as well as any incidence of arrthythmia among critically ill adult patients administered with oral caffeine 2. To study the feasibility of the study. Specifically, we will observe and examine factors and challenges (such as from the inclusion/exclusion criteria, caregiver's willingness to participate) that influence recruitment 3. To estimate the duration of mechanical ventilation with the use of oral caffeine (dose: 5mg/kg/dose twice daily) in adult patients who are critically ill. 1.1 Secondary Objectives The secondary objectives are: (a) To describe the ICU mortality, 30-days mortality, ICU length of stay, GCS, incidence of re-intubation, incidence of terminal extubation and need for tracheostomy among critically ill adult patients administered with oral caffeine Hypothesis: 1. Oral caffeine is safe for use for adult ICU patients with depressed GCS at the selected dose. 2. It is feasible to recruit the stipulated study population from SGH and SKH within the timeframe of the study. Proposed Trial Design: We propose a pilot multi-center, single arm trial of 10 patients with depressed GCS, assigned to receive oral caffeine. 10 subjects from SGH and SKH who are on mechanical ventilation with depressed GCS will be recruited into this study. No randomisation and blinding will be carried out in this study. Planned Trial Interventions: Patient will receive oral caffeine through their feeding tube, 5mg/kg/dose twice daily. Oral caffeine solution (colorless and odorless) will be prepared by pharmacy laboratory and supplied in amber glass bottle. Subject Consent: Consent will be obtained from patient's Legally Appointed Representative(LAR) if available, or the next of kin within 72 hours following inclusion and exclusion criteria screening. 1.1 Inclusion Criteria 1. Adult patients (≥ 21 years old), 2. Patients with encephalopathy (GCS ≤ 8) limiting extubation, where encephalopathy is deemed by clinician to be unresponsive to treatment or not eligible for treatment to reverse the encephalopathy (eg. transplantation) or if no treatment exists, and 3. Patients who are not planned for any surgical procedures within 24 hours 4. Patients on mechanical ventilation (intubated) 5. Patients who are not on sedative agents for at least 24 hours (exception for low dose fentanyl of up to 30mcg/h and dexmedetomidine of up to 0.5mcg/kg/h for analgesia/sedation/tube tolerance) For patients with primary CNS lesions, neurologist or neurosurgeon approval will be obtained prior to recruitment. 1.2 Exclusion Criteria 1. Known allergy or adverse reactions from caffeine, 2. Pregnant women, 3. Breast-feeding women, 4. Patients with uncontrolled cardiac arrhythmias, 5. Patients with uncontrolled hypertension, 6. Patients with hyperactive delirium, 7. Patients with chronic kidney disease (CKD, any stage) who received midazolam or morphine infusion during their ICU stay, 8. Patients who received barbiturate coma, 9. Patients who are on theophylline, aminophylline, doxapram or psychotropic agents at the point of screening for recruitment, 10. Patients with feed intolerant, short bowel syndrome, or 11. Patients with active seizures 1.3 Subject Replacement Subjects who drop out from the study (due to reasons other than those stipulated under section 4.4.1: discontinuation criteria) will be replaced with new recruitment. STUDY DESIGN 2.1 Randomisation and Blinding No randomisation and blinding will be carried out in this study. 2.3 Study Visits and Procedures 2.3.1 Screening Visits and Procedures Study subjects will be identified through referral by the attending ICU medical team or weekly patient screening. Potential subjects will be reviewed by one of the study team members for recruitment eligibility, according to the study inclusion and exclusion criteria. 2.3.2 Study Visits and Procedures Recruitment and subsequent follow up for study purpose will only be done in inpatient setting. Data collection form and schedule are as follow. Study subjects will be followed up for 30 days post recruitment or until hospital discharge, whichever earlier. All parameters collected are part of standard of care, no additional test required for the purpose of this study. Study feasibility data will be collected from screening and recruitment logs. Potential drug-drug interaction with oral caffeine will be monitored throughout the study period: 1. CYP1A2 enzyme inhibitors and inducers to be taken with caution/prohibited 2. CYP1A2 substrates to be taken with caution/prohibited Duration of follow up: Patient clinical status will be monitored on daily basis until 30 days after recruitment or discharge from hospital, whichever earlier. Data collection: Data collection will be done prospectively.

Recruitment information / eligibility

• Status: Suspended
• Enrollment: 10
• Est. completion date: December 31, 2025
• Est. primary completion date: December 31, 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years to 130 Years

Eligibility

Inclusion Criteria:

1. Adult patients (= 21 years old),

2. Patients with encephalopathy (GCS = 8) limiting extubation, where encephalopathy is deemed by clinician to be unresponsive to treatment or not eligible for treatment to reverse the encephalopathy (eg. transplantation) or if no treatment exists, and

3. Patients who are not planned for any surgical procedures within 24 hours

4. Patients who are not on sedative agents for at least 24 hours (exception for low dose fentanyl of up to 30mcg/h and dexmedetomidine of up to 0.5mcg/kg/h for analgesia/sedation/tube tolerance)

• For patients with primary CNS lesions, neurologist or neurosurgeon approval will be obtained prior to recruitment.

Exclusion Criteria:

1. Known allergy or adverse reactions from caffeine,

2. Pregnant women,

3. Breast-feeding women,

4. Patients with uncontrolled cardiac arrhythmias,

5. Patients with uncontrolled hypertension,

6. Patients with hyperactive delirium,

7. Patients with chronic kidney disease (CKD, any stage) who received midazolam or morphine infusion during their ICU stay,

8. Patients who received barbiturate coma,

9. Patients who are on theophylline, aminophylline or psychotropic agents at the point of screening for recruitment,

10. Patients with feed intolerant, short bowel syndrome, or

11. Patients with active seizures

Related Conditions & MeSH terms

• Brain Diseases
• Depression
• Encephalopathy

Intervention

Drug:
• Caffeine Citrate 20 MG/ML Oral Solution
Caffeine syrup will be prepared by pharmacy laboratory and kept refrigerated (2-8C), to be used within 1 month from the date of preparation by pharmacy laboratory.

Locations

Country	Name	City	State
Singapore	Singapore General Hospital	Singapore

Sponsors (2)

Lead Sponsor	Collaborator
Singapore General Hospital	Sengkang General Hospital

Country where clinical trial is conducted

Singapore, 

References & Publications (1)

Bright M, Raman V, Laupland KB. Use of therapeutic caffeine in acute care postoperative and critical care settings: a scoping review. BMC Anesthesiol. 2021 Mar 31;21(1):100. doi: 10.1186/s12871-021-01320-x. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Duration of mechanical ventilation	Duration of mechanical ventilation in days	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	ICU mortality	Mortality in the ICU (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	30-days mortality	Mortality within 30 days (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	ICU length of stay	Length of ICU stay in days	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Blood pressure	Blood pressure in mmHg	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Heart rate	Heart rate in beats per minute	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Incidence of arrhythmia	Incidence of arrhythmia reported (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	GCS	Glasgow coma scale	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Incidence of re-intubation	Need for re-intubation following an extubation (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Incidence of terminal extubation	Terminal extubation in the ICU (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier
Secondary	Need for tracheostomy	Need for tracheostomy (yes or no)	From the start of study drug with follow up period of 30 days or until hospital discharge, whichever earlier