CNS7056-022
Research type
Research Study
Full title
Phase III confirmatory efficacy and safety trial of remimazolam (CNS7056) compared with propofol for intravenous anaesthesia during elective surgery
IRAS ID
247961
Contact name
Kariem El-Boghdadly
Contact email
Sponsor organisation
PAION UK Limited
Eudract number
2018-000174-29
ISRCTN Number
ISRCTN00000000
Clinicaltrials.gov Identifier
Duration of Study in the UK
0 years, 7 months, 27 days
Research summary
Research Summary
This clinical trial investigates a new drug Remimazolam that leads to loss of consciousness and maintain unconsciousness during the general anaesthesia that is required to perform the surgical procedure. During this clinical trial, remimazolam is compared with propofol which is approved for the use in general anaesthesia. Participants will obtain either remimazolam or propofol and will not be informed about the treatment allocation (single blinded study). The maximum trial duration for any patient will be up to 30 days.
An overall sample size of 452 patients will be randomised. In addition, 1 subject per each of the 2 treatment arms will be recruited in the trial per site but not included in the randomisation scheme in order for the site personnel to familiarise with the trial procedures and remimazolam. In total, up to 500 patients will be enrolled in the trial.Summary of Results
SUMMARY OF CLINICAL TRIAL RESULTS FOR LAYPERSONSCNS7056-022
TABLE OF CONTENT
Page
1 CLINICAL TRIAL IDENTIFICATION 3
1.1 Title of the trial 3
1.2 Protocol number 3
1.3 EU trial number in the European Union 3
1.4 Other identifiers 3
2 NAME AND CONTACT OF SPONSOR 3
3 GENERAL INFORMATION ABOUT THE CLINICAL TRIAL 4
3.1 Where the trial was conducted 4
3.2 When the trial was conducted 4
3.3 The main objectives of the trial and reasons for conducting it 4
4 POPULATION OF PATIENTS 5
4.1 The number of patients included in the trial 5
4.2 Age group and gender breakdown 5
4.3 Inclusion and exclusion criteria 5
5 INVESTIGATIONAL MEDICINAL PRODUCTS USED 6
6 DESCRIPTION OF ADVERSE REACTIONS AND THEIR FREQUENCY 7
7 OVERALL RESULTS OF THE CLINICAL TRIAL 7
8 COMMENTS ON THE OUTCOME OF THE CLINICAL TRIAL 8
9 INDICATION IF FOLLOW UP CLINICAL TRIALS ARE FORESEEN 8
10 INDICATION WHERE ADDITIONAL INFORMATION COULD BE FOUND 81 CLINICAL TRIAL IDENTIFICATION
Researchers look at the results of many trials to decide which drugs work best and are safest for patients. It takes participants in many trials all around the world to advance medical science.
This summary only shows the results from this one trial. Other trials may find different results.
1.1 Title of the trial
Phase III Confirmatory Efficacy and Safety Trial of Remimazolam (CNS7056) Compared with Propofol for Intravenous Anaesthesia during Elective Surgery1.2 Protocol number
CNS7056-022
1.3 EU trial number in the European Union
2018-000174-29
1.4 Other identifiers
ClinicalTrials.gov Identifier: NCT03661489
2 NAME AND CONTACT OF SPONSOR
PAION UK Limited
Kew Road 5, Parkshot House, Unit 302, Richmond
TW9 2 PR London, England
Tel. +49 241 4453 0
email: info@paion.com
3 GENERAL INFORMATION ABOUT THE CLINICAL TRIAL
3.1 Where the trial was conducted
This trial took place in the following countries:
• Belgium
• Switzerland
• Germany
• France
• Italy
• The Netherlands
• United Kingdom
3.2 When the trial was conducted
The trial started in July 2018 and ended in April 2020.
The trial was ended earlier than planned because of the COVID-19 pandemic which took the time of the doctors and nurses in the hospitals and left them no time for working on the trial. Moreover, visits of representatives of PAION to the clinics to check the paperwork of the trial and the storage and use of the trial drug were not possible.
At the time of the early stop of the trial, a total of 409 patients were enrolled. The initial plan was to enrol 512 patients. This included 2 practice patients at each hospital, designed to give the doctors and nurses the opportunity to become familiar with the study drug and study procedures (see Section 5).
3.3 The main objectives of the trial and reasons for conducting it
The trial was conducted as part of the research on a new drug called remimazolam. Remimazolam is a drug from a well-known class of drugs that is called benzodiazepines. Other drugs from that class are in regular, worldwide use since several decades. The main general effect of benzodiazepines is to make a person calm or sleepy.
Remimazolam makes a person sleepy or even unconscious, depending on how much of it is given. The purpose of the trial was to cause and observe the unconsciousness secondary to remimazolam. Several machines were used to collect data, for example machines that measure how unconscious the patient was and blood pressure.
The main goals were to prove that remimazolam works as well as a standard drug used for causing unconsciousness (efficacy), and to prove that the blood pressure is more stable during unconsciousness caused by remimazolam compared to a commonly used medication used for causing unconsciousness (safety). Many anaesthetic medications can cause a large fall in the patient’s blood pressure. This can have serious consequences to the patient’s health.
For these purposes, remimazolam was compared with a drug called propofol. Propofol is the drug that is currently used most often to create unconsciousness in patients who undergo an operation. Propofol is given directly into a vein like remimazolam which was another reason why remimazolam was compared with propofol and not to other types of drugs, for example gases that cause unconsciousness.
The trial was done in patients with severe health problems. In these patients maintaining stable blood pressure during the operation is very important for their health during and after the operation.
4 POPULATION OF PATIENTS
4.1 The number of patients included in the trial
• in Belgium: 52
• in Germany: 154
• in France: 14
• in Italy: 26
• in The Netherlands: 46
• in total in the entire European Union: 292
• in countries outside the European Union (Switzerland, United Kingdom): 117
4.2 Age group and gender breakdown
Of 409 patients taking part in the trial, 291 patients were given remimazolam (the ‘remimazolam group’) and 118 patients were given propofol (‘the propofol group’). In the remimazolam group, 209 (71.8%) patients were male. In the propofol group, 83 (70.3%) patients were male. The average age was between 68 and 69 years in both groups. All 409 enrolled patients were included in the general analyses for safety.
For the analysis of efficacy and the stability of blood pressure, only data from non-practice patients was used. This subset of patients was called the Full Analysis Set (the ‘FAS’). The FAS remimazolam group included 270 patients of which 195 (72.2%) patients were male. The FAS propofol group included 95 patients of which 70 (73.7%) patients were male. The average age was between 68 and 69 years in both FAS groups.
4.3 Inclusion and exclusion criteria
Patients could be enrolled in the trial if the following conditions were met:
• Planned operation that was expected to take at least 90 minutes and which required the patient to be anaesthetised.
• No operation due to a sudden need / emergency.
• Age at least 18 years.
• Known severe chronic health problems that make a stable blood pressure important.
• No plan to cause local numbness (local anaesthesia) in addition to the unconsciousness.
• No illnesses that would have a strong effect on the patient’s medical condition during the unconsciousness and also on the goals of the trial, for example very high blood pressure. A list of illnesses not allowed in this trial was given to all participating doctors.
• No operations which required that the patient was laid down on the operation table in a way that changed the blood pressure notably and for a longer period of time, for example the so-called beach chair position.
• No pregnant or breast-feeding women.
5 INVESTIGATIONAL MEDICINAL PRODUCTS USED
The following drugs were used:
• Remimazolam, to be given directly into a vein before and during the operation.
OR
• Propofol 2% emulsion, to be given directly into a vein before and during the operation.
There were rules on how to use remimazolam or propofol, to keep the patient unconscious. In addition, there were rules on how to use other drugs that are used during routine anaesthesia, for example drugs that stop pain.
Patients were assigned by chance (randomisation) to receive either remimazolam or propofol. Of 4 patients, 3 patients were assigned to remimazolam and one patient was assigned to propofol.
The first 2 patients of each participating hospital were not assigned the study medication by chance (practice patients), but instead, the first patient of each hospital was assigned to propofol and the second patient of each hospital was assigned to remimazolam. This was done to give the doctors and nurses the opportunity to learn how the trial works.
This trial was single-blind. This means the patients did not know which study medication they received, but the doctors did know.
The trial started up to 28 days prior to the operation (for the purpose of collecting health data from partaking patients prior to the operation) and ended on the day after the operation.
The design of the trial including the planned evaluations of the trial data was laid down in a trial plan.
6 DESCRIPTION OF ADVERSE REACTIONS AND THEIR FREQUENCY
Unwanted medical events can happen during a trial. If a doctor suspects that an individual event was caused by a trial drug, this event is called a side effect.
In the trial reported here, side effects occurred in 197 of 291 patients (67.7%) in the remimazolam group and in 89 of 118 patients (75.4%) in the propofol group.
The following side effects were reported in at least 1 of 20 patients (5%) of the remimazolam group and/or the propofol group:
Remimazolam Propofol
Blood pressure decreased 33 patients (11.3%) 13 patients (11.0%)
Low blood pressure 120 patients (41.2%) 60 patients (50.8%)
Low blood pressure due to unconsciousness and/or operation 19 patients (6.5%) 9 patients (7.6%)
Slow heart beat 27 patients (9.3%) 20 patients (16.9%)
Prolonged drug effect 21 patients (7.2%) none
Nausea (feeling sick on the stomach) 12 patients (4.1%) 8 patients (6.8%)Side effects were regarded as serious if they were life-threatening or if they prolonged the time a patient needed to stay in the hospital (the patients were in the hospital because of their operation already). Serious side effects were reported for 13/291 patients (4.5%) on remimazolam and 3/118 (2.5%) patients on propofol. Delirium was the only type of serious side effect that was reported for more than 1 in 100 patients (1%). Delirium is a state of being puzzled. Patients with delirium do not understand where they are and why and what is happening around them. In the remimazolam group, 6/291 patients (2.1%) suffered from delirium for a short period of time after waking up after the operation. No patient in the propofol group suffered from delirium.
No patient died during the trial.
7 OVERALL RESULTS OF THE CLINICAL TRIAL
At the time of the early stop of the trial, 365 patients were enrolled and assigned to remimazolam or propofol, by chance. Based on the knowledge that was available before the start of this trial, this number of patients was sufficient to do the planned analyses.
Desired effects (efficacy): the ability of remimazolam to make patients unconscious and to keep them unconscious for the duration of the operation was similar to propofol. From the fine details of the course of the unconsciousness over time (depth of unconsciousness and need for other drugs), it became clear that dosing remimazolam up and down based on the needs of an individual patient worked as needed. However, dosing propofol up and down worked better when looking at the fine details. When the use of remimazolam was ended, patients woke up slower than after propofol.
Undesired effects (safety):
• Stability of the blood pressure: Remimazolam was proven to have a less negative impact on blood pressure in comparison to propofol.
• Side effects: See Section 6.
• Pain on injection: patients reported that the injection of remimazolam caused no pain while the injection of propofol did cause pain according to some of the patients.
• From blood tests and electrocardiogram, no difference between the treatment groups became apparent regarding safety of remimazolam and propofol, respectively.
8 COMMENTS ON THE OUTCOME OF THE CLINICAL TRIAL
The results of the trial confirmed that remimazolam can start and maintain unconsciousness as reliably as propofol. Moreover, the blood pressure was more stable during unconsciousness caused by remimazolam in comparison to propofol.
Almost all doctors who took part in this trial used remimazolam for the first time. It is assumed that doctors will learn over time how to change the dose of remimazolam so the patients remain at the ideal level of unconsciousness. This experience already exists for propofol, a medicine which is used in operations on a daily basis. Moreover, doctors may learn how to dose remimazolam towards the end of an operation so that a patient wakes up quicker than seen in this trial.
The results regarding the general safety of remimazolam were in line with what was already known about remimazolam, what was seen in other clinical trials with remimazolam and what was already known about the class of benzodiazepines.
9 INDICATION IF FOLLOW UP CLINICAL TRIALS ARE FORESEEN
The clinical research on remimazolam causing sleepiness or unconsciousness continues. Results of completed further clinical trials are reported to the authorities in charge and to the public on an ongoing basis.
10 INDICATION WHERE ADDITIONAL INFORMATION COULD BE FOUND
More information on remimazolam can be found on the internet/online via
https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.paion.com%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C1928f117d5f7413ce53108da2eb57890%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637873654182166939%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=GQNVR16B0OjHKBNNwEJFbwBvPbW%2FOrkwJKveDJ8KTy0%3D&reserved=0 and https://eur03.safelinks.protection.outlook.com/?url=http%3A%2F%2Fwww.clinicaltrialsregister.eu%2F&data=05%7C01%7Capprovals%40hra.nhs.uk%7C1928f117d5f7413ce53108da2eb57890%7C8e1f0acad87d4f20939e36243d574267%7C0%7C0%7C637873654182166939%7CUnknown%7CTWFpbGZsb3d8eyJWIjoiMC4wLjAwMDAiLCJQIjoiV2luMzIiLCJBTiI6Ik1haWwiLCJXVCI6Mn0%3D%7C3000%7C%7C%7C&sdata=qJWfvOEQEdAzjfEamlDrKF%2FYCij%2BD%2BP65c%2FUEOGgX7k%3D&reserved=0REC name
London - Chelsea Research Ethics Committee
REC reference
18/LO/0989
Date of REC Opinion
23 Jul 2018
REC opinion
Further Information Favourable Opinion