Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT02698969 |
| Other study ID # |
EUDRACT 2013-004-787-62 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
February 15, 2016 |
| Last updated |
October 24, 2016 |
| Start date |
November 2014 |
| Est. completion date |
July 2017 |
Study information
| Verified date |
October 2016 |
| Source |
University of Florence |
| Contact |
Chiara Adembri, MD |
| Phone |
+390554271101 |
| Email |
chiara.adembri[@]unifi.it |
| Is FDA regulated |
No |
| Health authority |
Italy: The Italian Medicines Agency |
| Study type |
Interventional
|
Clinical Trial Summary
Diaphragm ultrasonography as a diagnostic tool in order to demonstrate the superiority of
Sugammadex vs. AChEI in facilitating post-operative neuromuscular recovery.
Description:
The proposed study will be a prospective, double-blind, single center randomized study
performed in 60 patients with ASA physical status I-II, between 18-80 years old, undergoing
dNMB with rocuronium during ear nose and throat (ENT) surgery. Randomization will be
performed using a table created from the website www.randomization.com, and patients will be
divided equally into two groups: Treatment with Sugammadex (SUG group) or treatment with
Neostigmine (NEO group). Exclusion criteria will include: A history of hepatic or renal
disease, chron-ic or acute alcoholism, allergy or hypersensitivity to Sugammadex and/or
atropine or Neostigmine, current medications with CNS effects, a history of neurologic
disease, diaphragmatic palsy, pregnancy or nursing arrhythmias. Continuous neuromuscular
monitoring will be performed using TOF ratios obtained from ad-ductor pollicis muscle. At
the conclusion of the surgical procedure, patients will receive either Neostigmine (NEO
group) or Sugammadex (SUG group) for NMB reversal. The physician who will administer the
study drugs will insure that is per-formed on an open-label (non-blinded) basis. All
patients showing a TOF ratio ≥0.9 will be extubated. Diaphragmatic function (assessed by
ultrasonographic evaluation of the TF and amplitude of excursion) will be evaluated in each
subject at the following time points:
1. Prior to induction of general anesthesia.
2. At the conclusion of the surgical procedure when TOF ratio is 0.9.
3. 15 and 30 minutes after discharge from the operating theatre. The physician who will
perform the ultrasound scan will be different from the one who involved with
administration of the drug for NMB reversal and the former will be blinded with respect
to treatment received by patients. It is likely that, despite a TOF value greater than
0.9, higher diaphragm recovery will occur earlier and last longer when reversal of the
NMB is achieved using Sugammadex (a specific antagonist) when compared with Neostigmine
(a non-specific reversal).
In order to standardize the anesthetic technique, no premedication will be administered to
any patient candidate to undergo to microlaryngoscopy procedure. Besides each individual
enrolled will receive neuromuscular monitoring with ulnar nerve stimulation with TOF Watch®
(Organon, Oss, Netherlands). The device will be calibrated pre-operatively and parameters
set using standard train of four (TOF) methodology after administration of hypnotic drug
prior to muscle relaxation. Standard induction of general anesthesia will be performed using
intravenous (iv) fentanyl (2 mcg kg-1), propofol (2 mg kg-1), and rocuronium (0.6 mg kg-1).
Tracheal intubation will be performed when the patient fails to register signals with TOF.
Rocuronium (0.15 mg kg-1) will be re-administered when PTC elicits more than 5 twitches in
order to maintain a dNMB. Sevoflurane will be administered at1.0 MAC in an air/oxygen
mixture. Fentanyl will be titrated with a bolus of 0.5 mcg kg-1 every 30 minutes to maintain
analgesia. Prior to induction of anesthesia, ultrasonography diaphragm evaluation will be
performed using an ESAOTE ultrasound machine (ESAOTE MyLab, Genova, Italy) by assessing the
TF and amplitude of excursion. With the spontaneously breathing patient in semi-recumbent
position, the amplitude of excursion will be evaluated following the method of Kim et al (7)
using a 3.5-MHz ultrasound probe placed over the intercostal space above the 10th rib in the
right mid-axillary line for the right diaphragm and the left mid-axillary line for the left
diaphragm. The liver or spleen will be used as a window for each hemi-diaphragm. A
two-dimensional mode will be used to find the best approach and to select the exploration
line of each hemi-diaphragm. With the probe fixed on the chest wall during respiration, the
ultrasound beam will be directed to the hemi-diaphragmatic domes at an angle of not less
than 70°. During inspiration, the normal diaphragm contracts and moves caudally toward the
transducer; this will be recorded as an upward motion of the M-mode tracing. The amplitude
of excursion will be measured on the vertical axis of the tracing from the baseline to the
point of maximum height of inspiration on the graph. Three measurements will be performed
for each patient and averaged for each side at each time point of the protocol (7).
Moreover, TF will be assessed following the method of Vivier et al (6) with a linear high
frequency probe set at 12 Mhz. The diaphragm will be located with same method described
above and the zone of apposition will assessed at 0.5-2 cm below the costophrenic sinus. The
inferior border of the costophrenic sinus will be identified at end-inspiration as the zone
of transition from the artifact representation of normal lung (the lung sliding) to the
visualization of diaphragm and liver.
The diaphragm thickness will be recorded in time motion (TM) mode. The diaphragm will be
outlined using the two clear bright parallel lines of the pleural and peritoneal membranes.
Measurements will be averaged out of three or more consecutive breaths on the last valid
image recorded at the end of each period (6) .At the conclusion of the surgical procedure
and when TOF neuromuscular monitoring shows a minimum of 2 twitches, patients will randomly
receive, as described above, either (NEO Group) iv Neostigmine 50 µg kg-1 and atropine 15 µg
kg-1 or (SUG group) iv Sugammadex 2 mg kg-1 to reverse residual curarization. Extubation
will be performed when all of the following criteria are met: Patient is awake and executes
simple commands, shows regular respiratory pattern with a tidal volume of 6-7 mL/kg referred
to ideal body weight (IBW) and a TOF ratio ≥0.9. During the period preceding a TOF ratio >
0.9 , bilateral diaphragm ultrasonography evaluating amplitude of excursion and TF will be
performed to assess muscle recovery in spontaneous breathing patients. These measurements
will be compared with baseline muscle assessment. Three additional diaphragm ultrasound
scans will be performed 15 and 30 minutes after discharge from operating theatre. Follow up
will be performed to document every adverse event and complication that occurs until
discharge from the hospital.
Data will be collected by the use of paper CRF pages. Data entry will be performed at one
central site that will maintain the overall database and will perform and be responsible for
the data analysis.
The study will be conducted within 8 months -1 year from approval from our ethical
committee. A preliminary report will be completed and submitted after the first six months
of data collection.
Data will be collected by the use of paper CRF pages. Data entry will be performed at one
central site that will maintain the overall database and will perform and be responsible for
the data analysis. All the compiled CRFs will be archived. In order to eliminate possible
data entry errors, individual data will be compared to a range of plausible values. After
data entry, automated checks, that are defined beforehand (a priori), will be performed to
evaluate internal inconsistencies, range errors, or missing data. For each
atypical/out-of-range/missing data, a query will be automatically sent to the investigator.
Once all the queries are solved, the database will be locked and used for statistical
analysis.Statistical analysis will be performed in collaboration by the Department of
Statistics of the University of Florence. Complete data will not be unblinded until the
external medical and statistics review have been completed.
Data will be collected and a single statistical analysis will be performed at the completion
of the study using an intention to treat (ITT) analysis. With regard to the primary
endpoint, differences between the two groups with respect to distribution of muscle function
recovery after deep muscular blockade will be subjected to non-parametric tests depending on
the characteristics of outcome distribution. To compare the primary endpoint between the 2
groups, the data will be analysed using Wilcoxon rank sum test for two independent samples
as they are expected to be continuous and not normally distributed. As a sensitivity
analysis, parametric tests will potentially be employed after thorough evaluation of the
validity distribution assumptions.
The ultrasonography and TOF data will be summarized by drug treatment group as mean,
standard deviation, quintiles, and minim and maximum values. In addition, two-sided 95%
confidence intervals will be calculated on the comparison between the two groups for the
main descriptive parameters of the primary and secondary variables.
In order to compare the different percentage of respiratory events in the two arms studied,
a chi square test will be performed.
Finally, descriptive statistics of all variables describing characteristics of the patients
enrolled in the study and of patients excluded from the study will be produced. The mean,
median, standard deviation and range will be calculated for continuous data by drug
treatment group. For categorical variables, frequency counts and percentages will be
calculated.
Power/Sample Size:
Because this is the first clinical trial that proposes to evaluate this endpoint, no
published data are available at this time. However, assuming a 25% of difference of TF
between groups would be clinically meaningful, a confidence interval of 95% and power 80%,
sample size calculation provided by StatCalc EPI INFO ver 7.0 (Center for Diseases Control,
Atlanta, GA, USA) considered 28 patients for each group fundamental to reach the endpoint
predefined. This proposal requests funding for a pilot study, with a double blind design,
where participants will be randomly enrolled to receive Sugammadex or Neostigmine with a 1:1
allocation using the standardized table created with the website www.randomization.com.
