Condition category
Respiratory
Date applied
08/10/2017
Date assigned
30/10/2017
Last edited
13/10/2017
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Background and study aims
Several diseases may induce severe acute respiratory failure. This life-threatening condition may be stabilised with mechanical ventilation (a machine that inserts a tube in provide air to the lungs). In some patients with complicated breathing problems require sedation and paralysis (being put to sleep). This is usually done by being given neuromuscular blocking agents (NMBAS) a type of anaesthesia that puts the patients under sedation and paralysis. Recently the introduction of Cisatrex®, the generic of the brand name Nimbex®, provided an opportunity to substitute cisatracurium to other NMBAs. Because of the physicians’ reluctance to prescribe generics and all the controversies surrounding, authors hypothesized that a proof of safety and efficacy of Cisatrex® compared to its original brand-name could be of an invaluable support to reassure the physician while using Cisatrex®. The aim of this study is to compare the efficacy and tolerance of the two different paralysis agents Nimbex® and Cisatrex®.

Who can participate?
Adults aged 18 and older who are admitted to the ICU with severe acute respiratory failure with severe hypoxemia.

What does the study involve?
After a short period of stabilization under optimal analog-sedation. Patients are assigned randomly to receive one of the two drugs intravenously. They are subsequently monitored for the efficacy by a neurostimulator each 5 minutes for 3 hours period each drug.

What are the possible benefits and risks of participating?
There are no direct benefits with participation. There are risks with many medical procedures, however the present study deals with rottenly recommended drugs that are efficient and well tolerated. In several cases this may induce reversible cardiocirculatory disorder such as bradycardia or hypotension.

Where is the study run from?
Farhat Hached University Hospital (Tunisia)

When is the study starting and how long is it expected to run for?
July 2016 to March 2017

Who is funding the study?
Farhat Hached University Hospital (Tunisia)

Who is the main contact?
Professor Mohamed Boussarsar

Trial website

Contact information

Type

Scientific

Primary contact

Prof Mohamed Boussarsar

ORCID ID

http://orcid.org/0000-0002-7557-2156

Contact details

Medical Intensive Care Unit
Farhat Hached University Hospital
1st
Rue Ibn Al Jazzar
Sousse
4000
Tunisia

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

01072016

Study information

Scientific title

Compared efficacy and tolerance of the neuromuscular blockade induced by original brand-name (Nimbex®) and generic (Cisatrex®) of cisatracurium in mechanically ventilated critically ill patients: A crossover double-blind randomized study

Acronym

Study hypothesis

Cisatracurium original brand-name (Nimbex®) is better than his generic (Cisatrex®).

Ethics approval

Medical Ethics’ and Research Committee of Farhat Hached University Hospital in Sousse, 01/07/2016, ref: IRB registration number assigned by OHRP: IRB00008931

Study design

Crossover double-blind randomised trial

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

See additional files

Condition

Patients admitted to ICU, under optimized sedation and ventilation, for hypoxemic acute respiratory failure with a PaO2/FIO2 < 200 and requiring paralysis to improve gas exanges and offset patient-ventilator asynchronies.

Intervention

Participants admitted to the ICU under optimised sedation and ventilation for hypoxemic acute respiratory failure a PaO2/FIO2 < 200 and requiring paralysis to improve gas exanges and offset patient-ventilator asynchronies.

Neuromuscular blockade is induced respectively by the two cisatracurium forms during two successive periods, separated by a one-hour washout period. Neuromuscular function was monitored by a calibrated train-of-four (TOF) stimulation.

A pre-protocol test patient is performed in order to define the minimum delay for paralysis, recovery time, better intervals for monitoring and to train the co-investigator residents (NF, JA & SR) to monitor the different parameters and to get familiar with the form designed to collect these parameters. The same co-investigators monitored all the included patients to ensure the maximal consistency and homogeneity of the collected data.

After a one hour of the stabilisation period and referring to the current state-of-the-art targeting respiratory and hemodynamic stability, participants arre randomized to a double-blind inclusion for the order of infusion of the two products under study, based on the random table. The principal investigator (MB) implemented the random allocation sequence, enrolled and assigned participants to interventions. He pre-prepared the assigned drug and concealed the sequence until all interventions were performed. Co-investigators (NF, JA & SR), participants and care providers were blinded after assignment to interventions. Participants are randomised to receiving either one of two paralysis agents, either Nimbex® and Cisatrex®.

In all studied patients it was ensured within the study period that the patients displayed no significant patient-ventilator asynchrony.

Paralysis depth is monitored by TOF.

A short period of stabilization under effective analgo-sedation as assessed by RSS was performed.

The neuromuscular blockade drug is initiated, a continuous infusion of cisatracurium is started at a dose of 0.06mg.kg-1.h-1 and increased in increments of 0.03mg.kg-1.h-1 every 30min to reach and sustain a TOF at 2/4, with a maximum study time limited to two hours and a maximum dose of 0.18mg.kg-1.h-1 as assessed by the pre-protocol test patient and The 2002 “Clinical Practice Guidelines for Sustained Neuromuscular Blockade in the Adult Critically Ill Patient” updated in 2016.

During this same period, the following parameters were measured at the same intervals every five minutes (TOF, heart rate, systolic and diastolic blood pressures, and ventilatory parameters). The infusion of the first product is stopped after two hours to allow the elimination of the first active paralysis agent before the infusion of the second (wash-out period).

The one-hour wash-out period is chosen based on the pharmacodynamic properties of the product which suggest that its elimination would be rapid due to its metabolism by Hofmann elimination and as suggested by several studies which assessed a recovery time ranging from 45min to 68min. The wash-out period is checked to be quite sufficient to recover a TOF of 4/4 as demonstrated in the pre-protocol test patient. This same period would serve to monitor the recovery kinetics (recovery time) of the first product. At the end of the wash-out period, the second product was then introduced. Its effect and tolerance (hemodynamic tolerance and drug interaction) were monitored according to the same protocol.

Intervention type

Drug

Phase

Not Applicable

Drug names

Cisatracurium original brand-name (Nimbex®)
Cisatracurium generic (Cisatrex®)

Primary outcome measures

1. Paralysis delay is measured using the train of four (TOF) at baseline and each 5 minutes time interval till 2 hours
2. Recovery time is measured using the TOF after stopping paralysis agent and each 5 minutes time interval till 1 hour

Secondary outcome measures

1. TOF variability is measured using the changes of TOF responses at each interval time within the paralysis period and recovery time
2. Hemodynamic tolerance is measured using the variation in heart rate above 30% of the baseline value and/or a significant drop of systolic and/or diastolic blood pressures above 30% of the baseline values at each 5 minutes
3. Tolerance is measured using Drug interactions mainly with antibiotics, monitored within the 6 hours protocol period

Overall trial start date

01/07/2016

Overall trial end date

31/03/2017

Reason abandoned

Eligibility

Participant inclusion criteria

1. Patients admitted to the ICU with severe acute respiratory failure with severe hypoxemia (ratio of arterial oxygen partial pressure to fractional inspired oxygen (PaO2/FiO2) < 200),
2. Put under invasive mechanical ventilation with important patient-ventilator asynchrony and requiring paralysis despite deep analgo-sedation as assessed by RSS
3. Aged 18 and older

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Twenty-two patients

Participant exclusion criteria

1. Patients with history of allergy to cisatracurium
2. Malignant hyperthermia
3. Pregnancy
4. Neuromuscular disorders

Recruitment start date

01/07/2016

Recruitment end date

31/03/2017

Locations

Countries of recruitment

Tunisia

Trial participating centre

Farhat Hached University Hospital
Medical Intensive Care Unit 1st, Rue Ibn Al Jazzar
Sousse
4000
Tunisia

Sponsor information

Organisation

Farhat Hached University Hospital

Sponsor details

1st
Rue Ibn Al Jazzar
Sousse
4000
Tunisia

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

University/education

Funder name

Farhat Hached University Hospital

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Planned publication in a high-impact peer reviewed journal.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

15/10/2017

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes