Efficacy and Safety of Remifentanil for Mechanically Ventilated Patients in ICU

Efficacy and Safety of Remifentanil for Mechanically Ventilated Patients in Intensive Care: Multicenter, Random, Double-blind, Parallel, Positive Control Clinical Trials

Remifentanil has been approved by the FDA for continuation as an analgesic into the immediate postoperative period in adult patients under the direct supervision of an anesthesia practitioner in a postoperative anesthesia care unit or intensive care setting. However, National Medical Products Administration(NMPA) did not approve this indication. Therefore, the purpose of this study is to confirm the efficacy and safety of remifentanil in the analgesic therapy of critical ill patients in China.

Study Overview

• Status: Recruiting
• Conditions: Analgesia
• Intervention / Treatment: Drug: Fentanyl; Drug: Remifentanil

Detailed Description

The study was conducted in accordance with good clinical practice and with the guidelines set out in the Declaration of Helsinki. After approval from local and national ethics committees, patients from 17 centres in China were recruited. All patients were randomized, in a double-blind manner, to receive either a remifentanil-propofol regimen or a fentanyl-propofol regimen for analgesia and sedation in the ICU. The aim of the study was to achieve optimal sedation and patient comfort by maintaining an optimal Critical Care Pain Observation Tool (CPOT) score of 2, without clinically significant pain, until the start of the extubation process or for 72 hours, whichever occurred first. CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2).

• Study Type: Interventional
• Enrollment (Anticipated): 138
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Liu Ling, MD; Phone Number: 13851435472; Email: liulingdoctor@126.com

Study Locations

• China
  • Anhui
    • Hefei, Anhui, China, 230000
      • Recruiting
      • Anhui Provincial Hospital
      • Contact: Pan Aijun, MD; Phone Number: +8613866668786
  • Beijing
    • Beijing, Beijing, China, 100000
      • Recruiting
      • Beijing Tiantan Hospital, Capital Medical University
      • Contact: Zhou Jianxin, MD; Phone Number: +8613801183875
  • Chongqing
    • Chongqing, Chongqing, China, 404100
      • Recruiting
      • The First Affiliated Hospital of Chongqing Medical University
      • Contact: Zhou Fachun, MD; Phone Number: +8618502388799
  • Guangdong
    • Qingyuan, Guangdong, China, 511500
      • Recruiting
      • Qingyuan People's Hospital
      • Contact: Yang Jingwen, MD; Phone Number: +8613542498765
  • Guizhou
    • Guiyang, Guizhou, China, 550000
      • Recruiting
      • Affiliated Hospital of Guizhou Medical University
      • Contact: Shen Feng, MD; Phone Number: +8613511999117
    • Zunyi, Guizhou, China, 563000
      • Recruiting
      • Affiliated Hospital of Zunyi Medical University
      • Contact: Chen Tao, MD; Phone Number: +8615329112288
  • Hebei
    • Shijiazhuang, Hebei, China, 050000
      • Recruiting
      • The Fourth Hospital of Hebei Medical University
      • Contact: Hu Zhenjie, MD; Phone Number: +8613933856908
  • Henan
    • Zhengzhou, Henan, China, 450000
      • Recruiting
      • Henan Provincial People's Hospital
      • Contact: Qin Bingyu, MD; Phone Number: +8613633810677
    • Zhengzhou, Henan, China, 450000
      • Recruiting
      • First Affiliated Hospital of Zhengzhou University
      • Contact: Sun Tongwen, MD; Phone Number: +8613838516916
  • Hubei
    • Enshi, Hubei, China, 445000
      • Recruiting
      • Enshi Tujia and Miao Autonomous Prefecture Central Hospital
      • Contact: Li Dezhong, MD; Phone Number: +8615342885588
    • Yichang, Hubei, China, 443000
      • Recruiting
      • Yichang Central People's Hospital
      • Contact: Gong Xun, MD; Phone Number: +8615872549520
  • Hunan
    • Changsha, Hunan, China, 410000
      • Recruiting
      • The Third Xiangya Hospital of Central South University
      • Contact: Yang Mingshi, MD; Phone Number: +8613973139006
    • Changsha, Hunan, China, 410000
      • Recruiting
      • Xiangya Hospital of Central South University
      • Contact: Zhang Lina, MD; Phone Number: +8615874875763
  • Jiangsu
    • Nanjing, Jiangsu, China, 210009
      • Recruiting
      • Nanjing Zhong-Da Hospital, Southeast University
    • Yangzhou, Jiangsu, China, 225000
      • Recruiting
      • Northern Jiangsu People's Hospital
      • Contact: Zheng Rui qiang, MD; Phone Number: +8613952721411
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310000
      • Recruiting
      • Zhejiang Provincial People's Hospital
      • Contact: Sun Renhua, MD; Phone Number: +8613505710366
    • Wenzhou, Zhejiang, China, 325000
      • Recruiting
      • The First Affiliated Hospital of Wenzhou Medical University
      • Contact: Pan Jingye, MD; Phone Number: +8613566289666

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Invasive mechanical ventilation with endotracheal intubation
• Expected to continue mechanical ventilation for more than 12 hours
• Informed consent/assent was obtained from all patients or their representatives

Exclusion Criteria:

• Patients with a history of allergy to opioids, benzodiazepines, propofol, or alcohol/drug abuse were excluded from the study
• Patients who are known or suspected to be allergic to the study drug
• Patients whose expected survival time is less than 48h
• Patients receiving deep sedation (RASS≥-4)
• Patients using neuromuscular blocking agent
• Patients who cannot be assessed by RASS
• Patients with myasthenia gravis
• patients with bronchial asthma
• patients with abdominal compartment syndrome
• Patients who need surgery or tracheotomy during the study drug treatment period
• Women during pregnancy and lactation
• Patients who have used short-acting non-steroidal anti-inflammatory drugs within 6 hours
• Patients who have used long-acting non-steroidal anti-inflammatory drugs within 12 hours
• Patients with a history of chronic pain for more than 3 months or who are receiving regular analgesia for more than 3 months
• Patients who have used monoamine oxidase inhibitors within two weeks
• Patients who participate in any clinical trials as subjects within 1 month
• Patients with a history of drug abuse, drug abuse, alcohol abuse* and long-term use of psychotropic drugs within 2 years Alcoholism: Drinking more than 14 times/week (1 time=150ml wine or 360ml beer or 45ml spirits)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Remifentanil; Remifentanil analgesia combined with propofol sedation. Treatment was started in patients with an CPOT score of 2 or greater after completion of baseline assessments. All patients received an initial infusion of blinded opioid (placebo bolus dose(6ml) + 6ug/kg per hour infusion at 6 ml/hour). Optimal analgesia (CPOT score ≤2) was then targeted by titrating the infusion in 1.5 ml/hour increments (placebo bolus dose + 1.5ug/kg per hour rate increase).	Drug: Remifentanil; Dosage forms and strengths: 3 mL Vial/1 mg lyophilized powder. Manufacturer: Yichang Humanwell Pharmaceutical Co.,Ltd; Other Names: Remifentanil Hydrochloride for Injection
Active Comparator: Fentanyl; Fentanyl analgesia combined with propofol sedation. Treatment was started in patients with an CPOT score of 2 or greater after completion of baseline assessments. All patients received an initial infusion of blinded opioid (1ug/kg bolus(6ml) + 1ug/kg per hour infusion at 6ml/hour). Optimal analgesia (CPOT score ≤2) was then targeted by titrating the infusion in 1.5 ml/hour increments (1ug/kg bolus dose + 0.25ug/kg per hour rate increase).	Drug: Fentanyl; Dosage forms and strengths: 50 mcg/mL Fentanyl base/10 mL ampules. Manufacturer: Yichang Humanwell Pharmaceutical Co.,Ltd; Other Names: Fentanyl Citrate Injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
analgesia success rate(the proportion of subjects with successful analgesia to the number of subjects in each group)	Analgesia success is defined as: 1. No salvage analgesics were used during the administration of the study drug; 2 During the administration of the study drug, the time for the analgesia score of subjects to reach the standard (CPOT score ≤ 2) was greater than 70%. CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2).	From study drug administration to actual extubation , up to 72 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
During the study drug administration period, the subjects are in the proportion of optimal time(CPOT score≤2)	CPOT scoring criteria: Facial expressions(Relaxed, neutral=0; Tense=1; Grimacing=2); Body movements(Absence of movements or normal position=0; Protection=1; Restlessness/Agitation=2); Muscle tension(Relaxed=0; Tense, rigid=1; Very tense or rigid=2); Compliance with the ventilator or Vocalization(Tolerating ventilator or movement/Talking in normal tone or no sound=0; Coughing but tolerating/Sighing, moaning=1; Fighting ventilator/Crying out, sobbing=2).	From study drug administration to actual extubation , up to 72 hours
The number of times the remedial sedative drug propofol was used	Use the total times of propofol	From study drug administration to actual extubation , up to 72 hours
The proportion of subjects using the salvage sedative drug propofol	The proportion of subjects who using the salvage sedative drug propofol to the total subjects.	From study drug administration to actual extubation , up to 72 hours
The dosage of the remedial sedative drug propofol	Use the total dose of propofol	From study drug administration to actual extubation , up to 72 hours
Extubation time	The start of the extubation process until actual extubation	From the start of the extubation process until actual extubation , up to 72 hours
The success rate of wearing mechanical ventilator	The proportion of subjects who successfully wearing from mechanical ventilator to the total subjects.	From study drug administration to actual extubation , up to 72 hours
Wearing time from mechanical ventilation	Wearing time criteria: The primary disease is improved, and there is no new disease; no use of vasopressors or continuous application of sedative drugs; cough reflex during sputum suction; PEEP≤5cmH2O; PaO2/FiO2≥200mmHg; Minute ventilation<15L/min; 2-minute spontaneous breathing test and passed.	From study drug administration to wearing from mechanical ventilation, up to 72 hours
Duration of study drug use in ICU	The time from the start of the study drug administration to the time discharge ICU.	From study drug administration to the time discharge ICU , up to 72 hours
The proportion of subjects discharging the ICU	The proportion of subjects who discharge ICU to the total subjects.	From study drug administration to the time discharge ICU, up to 24 weeks
ICU mortality	The proportion of subjects who died during ICU admission to the total subjects.	From study drug administration to the time discharge ICU, up to 24 weeks
Hospital mortality	The proportion of subjects who died during hospital admission to the total subjects.	From study drug administration to the time discharge hospital, up to 24 weeks
Length of ICU stay	The number of days the subject stayed in the ICU	From administration to discharge ICU, up to 24 weeks
Length of hospital stay	The number of days the subject stayed in the hospital	From administration to discharge hospital, up to 24 weeks
The incidence of study drug-related Lower blood pressure	Lower blood pressure: mean arterial pressure (MAP) drops more than 25% from the baseline level or requires additional vasopressors;	From study drug administration to actual extubation , up to 72 hours
The incidence of study drug-related slow heart rate	Slow heart rate: HR<40bpm for less than 1 minute or HR<60 bpm for more than 1 minute;	From study drug administration to actual extubation , up to 72 hours
The incidence of study drug-related respiratory depression	Respiratory depression: RR<10 bpm or SpO2<90%	From study drug administration to actual extubation , up to 72 hours
Analysis of the cost-effectiveness between remifentanil and fentanyl	cost-effectiveness	From study drug administration to actual extubation , up to 72 hours

Collaborators and Investigators

• Sponsor: Southeast University, China
• Investigators: Study Chair: Yang Yi, MD, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University

Study record dates

Study Major Dates

• Study Start (Actual): June 10, 2021
• Primary Completion (Anticipated): December 30, 2022
• Study Completion (Anticipated): December 30, 2022

Study Registration Dates

• First Submitted: June 30, 2021
• First Submitted That Met QC Criteria: August 3, 2021
• First Posted (Actual): August 12, 2021

Study Record Updates

• Last Update Posted (Actual): August 11, 2022
• Last Update Submitted That Met QC Criteria: August 9, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: critical care; mechanical ventilation; safety; fentanyl; efficacy; sedation; analgesia; propofol; remifentanil; analgesia based sedation
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Central Nervous System Depressants; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; Analgesics, Opioid; Narcotics; Adjuvants, Anesthesia; Remifentanil; Fentanyl
• Other Study ID Numbers: ZDRF

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: No
• Studies a U.S. FDA-regulated device product: No