Contact information
Type
Scientific
Primary contact
Dr Andrew Kirkham
ORCID ID
Contact details
GlaxoSmithKline
Greenford Road
Greenford
Middlesex
UB6 0HE
United Kingdom
+44 (0)208 966 3919
andrew.jt.kirkham@gsk.com
Additional identifiers
EudraCT number
ClinicalTrials.gov number
Protocol/serial number
USA30206
Study information
Scientific title
Acronym
Study hypothesis
This randomised, double-blind study compared the safety and efficacy of remifentanil (REMI - 9 mcg/kg/h) with fentanyl (FEN - 1 mcg/kg + 1.5 mcg/kg/h). One hundred and ninety six Intensive Care Unit (ICU) subjects with normal renal function or mild renal impairment requiring mechanical ventilation were studied. A pre-defined dosing algorithm permitted initial titration of the opioid followed by the addition of propofol (0.5 mg/kg/h) if required. A REMI-based regimen was very effective in the provision of optimal sedation and analgesia. The mean % hours of optimal sedation was 88.3% in the REMI group. Similar results were observed when using FEN. There was no statistically significant difference in the overall between-subject variability in the duration of optimal sedation. However for those subjects who achieved a Sedation Agitation Scale (SAS) score of four, variability was significantly lower when using REMI.
Propofol was not required in 65% of subjects. When propofol was administered there was a trend towards less use in remifentanil subjects. The dosing algorithm facilitated rapid extubation in both treatment groups. REMI provided comparable haemodynamic stability compared to FEN. The adverse event profile observed for REMI was similar to FEN and was not unexpected for ICU subjects receiving an opioid agonist. The pharmacokinetic (PK) profile of REMI was unaltered in subjects with renal impairment. Although the elimination half-life of remifentanil acid was doubled and the clearance was reduced by half in subjects with mild renal impairment, no evidence of prolonged opioid effects were seen. REMI is therefore considered to effective and well tolerated in ICU subjects.
Ethics approval
Ethics approval received from local and national ethics committees.
Study design
Randomised controlled trial
Primary study design
Interventional
Secondary study design
Randomised controlled trial
Trial setting
Hospitals
Trial type
Treatment
Patient information sheet
Condition
Analgesia in the critically ill
Intervention
Assessment of sedation and pain scores with initial titration of the opioid to effect, monitoring of haemodynamics.
Intervention type
Drug
Phase
Not Specified
Drug names
Remifentanil, fentanyl
Primary outcome measure
Between-subject variability around the mean percentage of hours of optimal sedation (Sedation Agitation Scale [SAS] score of 4).
Secondary outcome measures
Efficacy:
1. Mean percentage of hours subjects were optimally sedated (SAS score of 4) during the treatment and post-treatment periods
2. Mean percentage of hours subjects were inadequately sedated (SAS score of 5, 6 or 7) during the treatment and post-treatment periods
3. Mean percentage of hours subjects were excessively sedated (SAS score of 1, 2 or 3) during the treatment and post-treatment periods
4. Mean percentage of hours subjects were dangerously agitated (SAS score of 7) during the treatment and post-treatment periods
5. Mean percentage of hours subjects were unarousable (SAS score of 1) during the treatment and post-treatment periods
6. Mean percentage of hours of no/mild pain during the treatment and post-treatment periods
7. Time between start of the extubation process and actual extubation
8. Total time on mechanical ventilation within the treatment period
9. Time between extubation and ICU discharge
10. Time from the start of study drug until ICU discharge
Other:
1. Weighted mean infusion rates of remifentanil, fentanyl and propofol
2. Total exposure to study opioid and propofol including frequency of opioid infusion rate changes, and propofol infusion rate changes (from starting the opioid infusion until it was discontinued)
3. Incidence of supplementary open-label propofol and fentanyl bolus doses administered for stimulating procedures during the treatment period
4. Incidence of open-label propofol and fentanyl bolus doses administered for rescue treatment during the maintenance phase
5. Incidence of supplementary open-label propofol, fentanyl, morphine and bupivacaine bolus doses administered for analgesia/sedation during the extubation and post-extubation phases
Safety:
1. Haemodynamic parameters during and after treatment (mean arterial pressure [MAP] and heart rate [HR])
2. Respiratory function (post-extubation only - respiratory rate [RR], fractional inspired oxygen concentration [FiO2] and peripheral oxygen saturation [SpO2])
3. Clinical adverse events
Pharmacokinetics:
Remifentanil and remifentanil acid blood concentrations.
Overall trial start date
12/07/1999
Overall trial end date
19/06/2000
Reason abandoned (if study stopped)
Eligibility
Participant inclusion criteria
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Admitted into the ICU within the previous 24 hours
2. Intubated and expected to require short-term mechanical ventilation (i.e. for at least a further 12 hours and up to 72 hours after starting the study drug infusion)
3. Aged over 18 years old
4. A female is eligible to enter and participate in this study if she is of:
4.1. Non-childbearing potential (i.e., physiologically incapable of becoming pregnant, including any female who is post-menopausal) or,
4.2. Child-bearing potential, has a negative pregnancy test (urine or serum) at screen, and agrees to one of the following:
4.2.1. Complete abstinence from intercourse from two weeks prior to administration of study drug, throughout the study, and for a time interval after completion or premature discontinuation from the study to account for elimination of the investigational drug (minimum of 7 days)
4.2.2. Female sterilisation
4.2.3. Sterilisation of male partner
4.2.4. Implants of levonorgestrel
4.2.5. Injectable progestogen
4.2.6. Oral contraceptive (combined or progestogen only)
4.2.7. Any intrauterine device (IUD) with published data showing that the highest expected failure rate is less than 1% per year (not all IUDs meet this criterion)
4.2.8. Any other methods with published data showing that the highest expected failure rate for that method is less than 1% per year
4.2.9. Barrier method only if used in combination with one of the above methods
5. Weighs an estimated 120 kg or less
6. Informed consent: a signed and dated written informed consent or assent must be obtained from the subject or the subject's legally acceptable representative, respectively, prior to study participation
7. Language: fluent and literate in the language spoken by the investigator and staff
Participant type
Patient
Age group
Adult
Gender
Both
Target number of participants
152
Participant exclusion criteria
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Concurrent medications:
1.1. Requires neuromuscular blocking agents to facilitate mechanical ventilation
1.2. Has or is likely to receive an epidural block during the maintenance phase
2. The use of remifentanil, fentanyl or propofol is contraindicated
3. Concurrent disease or disorder:
3.1. Has or is likely to require a tracheostomy within 96 hours after admission to the ICU
3.2. Has a neurological disease or other medical condition that may affect the ability to assess the SAS score and PI (e.g. stroke, stupor or coma, dementia)
3.3. Predicted creatinine clearance of <50 mL/min indicating moderate or severe renal impairment
3.4. Modified ICU admission simplified acute physiology score (SAPS) II score of greater than 43
4. Drug allergy: history of allergic hypersensitivity to fentanyl analogues, morphine, benzodiazepines or propofol
5. History of alcohol abuse
6. History of drug abuse: clinically significant abuse of opioid or sedative containing substances, defined as:
6.1. Patterns of substance intake consistent with disruption of normal function in society
6.2. Past or current impairment of organ function reasonably related to substance intake
7. Previous entry into this study or participation in any other investigational drug study within 30 days of randomisation
8. Concurrently participating in another clinical study in which the subject is or will be exposed to an investigational or a non-investigational drug or device
9. Protocol specified treatment regimens would be inappropriate for the management of the subject
10. The subject will have been in the ICU for longer than 24 hours at the time of starting the study drug infusion
Recruitment start date
12/07/1999
Recruitment end date
19/06/2000
Locations
Countries of recruitment
Belgium, Germany, Netherlands, Spain, United Kingdom
Trial participating centre
GlaxoSmithKline
Middlesex
UB6 0HE
United Kingdom
Sponsor information
Organisation
GlaxoSmithKline (UK)
Sponsor details
Greenford Road
Greenford
Middlesex
UB6 OHE
United Kingdom
+44 (0) 208 966 3919
andrew.jt.kirkham@gsk.com
Sponsor type
Industry
Website
Funders
Funder type
Industry
Funder name
GlaxoSmithKline (UK)
Alternative name(s)
GlaxoSmithKline plc., GSK
Funding Body Type
private sector organisation
Funding Body Subtype
corporate
Location
United Kingdom
Results and Publications
Publication and dissemination plan
Not provided at time of registration
Intention to publish date
Participant level data
Not provided at time of registration
Basic results (scientific)
Publication list
Results in http://www.ncbi.nlm.nih.gov/pubmed/14975049
Publication citations
-
Results
Muellejans B, López A, Cross MH, Bonome C, Morrison L, Kirkham AJ, Remifentanil versus fentanyl for analgesia based sedation to provide patient comfort in the intensive care unit: a randomized, double-blind controlled trial [ISRCTN43755713]., Crit Care, 2004, 8, 1, R1-R11, doi: 10.1186/cc2398.