Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03374514 |
| Other study ID # |
3233 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
Phase 3
|
| First received |
November 23, 2017 |
| Last updated |
December 27, 2017 |
| Start date |
August 9, 2017 |
| Est. completion date |
November 2018 |
Study information
| Verified date |
December 2017 |
| Source |
Hospital Italiano de Buenos Aires |
| Contact |
Federico A. Di Lella, MD |
| Phone |
541149581493 |
| Email |
federico.dilella[@]hospitalitaliano.org.ar |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
Hearing is the ability to perceive sounds through the ear. If the transmission of sound is
defective, the person suffers some degree of hearing loss. Cochlear Implants (CI) provide
partial hearing by stimulating auditory nerve cells.
The evaluation of the functionality of the CI is facilitated by several analysis tools, such
as the clinical calibration software. This offers the possibility of measuring electrical
impedances in the cochlea. The electrical impedance is the opposition to the current flow
between two electrodes. It is composed of two main elements: resistance and reactance. The
impedances in a cochlear implant are not stable over time. The value is minimal immediately
after surgery, and increases progressively in the first 2 to 3 weeks after the procedure due
to the immune response of the organism against a foreign body and the trauma of the array
insertion. Several authors have suggested the use of topical or intravenous corticosteroids
to decrease intracochlear fibrosis. The use of Dexamethasone could have a protective effect
by reducing the initial inflammatory response, apoptosis, and delayed fibrosis, which could
impact the impedance.
There is limited evidence on the effect of intra-surgical topical corticosteroids on the
impedance of the cochlear implant.
The aim of this clinical trial is to evaluate the impact of topical dexamethasone on the
electrical impedance of the cochlear implant, with special attention to the analysis of the
capacitive component. It will be carried out through an experimental, prospective, randomized
and double-blind study.
Objective To determine whether the use of topical dexamethasone in a single dose applied in
the tympanic cavity (middle ear) during cochlear implant surgery modifies the capacitive
component of the electrical impedance of the electrodes in the cochlea before the activation
of the cochlear implant.
Material and methods A phase 3 clinical trial will be conducted. The design is a parallel,
randomized, controlled and double-blind experimental study.
Expected impact The use of local dexamethasone during cochlear implant surgery would decrease
the inflammatory response, improving postoperative impedances.
Description:
Hypothesis The use of topical dexamethasone in a single dose applied to the tympanic cavity
during cochlear implant surgery modifies the capacitive component of the electrical impedance
of the electrodes in the cochlea during the first days of the postoperative period.
goals Primary objective To assess whether the use of topical dexamethasone in a single dose
applied to the tympanic cavity (middle ear) during cochlear implant surgery, prior to the
insertion of the electrode array in the cochlea modifies the capacitive component of the
electrical impedance of the cochlear implant. electrodes in the cochlea before activation of
the cochlear implant.
Secondary objectives To assess the safety and efficacy of the use of topical dexamethasone in
a single dose in the middle ear cavity during cochlear implant surgery.
To estimate the capacitive component of the electrical impedance of the electrodes in the
cochlea on a daily basis, from the day of surgery until the day of switching on, in two
groups of patients: experimental and placebo.
Materials and methods Design Phase 3 clinical trial design is an experimental parallel,
randomized, controlled, double blind assess the effect of the use of topical corticosteroids
on the electrical impedance of the electrodes in the cochlea after surgery will be performed
of cochlear implant surgery.
All patients diagnosed with severe to profound sensorineural hearing loss unilateral or
bilateral that its pathogenesis and pathophysiology are considered candidates for cochlear
implantation, will be evaluated as routine in our service, imaging, audiological and
psychological studies. Accomplished and accepted the nomination for the placement of one or
two cochlear implants will be offered the opportunity to participate in the protocol.
Patients will be selected and those who accept the invitation to participate, the study will
be randomly divided into two groups, an experimental group and a placebo group. Randomization
was performed in balanced way with a 1: 1 ratio between the branches. The randomisation list
will be in blocks of variable size between 2 and 6.
We will proceed as usual to the cochlear implant surgery, using the same anesthetic
technique, surgical approach and surgical procedure in any cochlear implant surgery.
Technique worldwide known and accepted as "minimally traumatic cochlear implant surgery" (see
section definitions below) is used.
The two study groups are:
Group Dexamethasone(DEX):topical administration of dexamethasone (20 mg / ml) in the eardrum
of the middle ear through the back tympanostomy, single dose during cochlear implant surgery,
prior to inserting the array of electrodes.
Group Placebo / Solution Physiological(SF):topical administration of isotonic sterile
physiological solution in the eardrum of the middle ear through the back tympanostomy,single
dose during cochlear implant surgery, prior to insertion of the array of electrodes .
After inserting the electrode array into the cochlea, proceed as usual measurements of the
electrical responses Intraoperative routine and supplemented with the closure and local
healing.
From the date of the surgical procedure and until the final activation of the implant
(usually 30 days), you will be asked the patient or family, you make two daily measurements
of the impedances of the electrodes, for which he was trained during the hospitalization the
day of surgery, the use of a simple software to be distributed for this purpose (CIDC -see
later-). The software installed on the computer from the patient can communicate through the
common communication interface Cochlear POD (used in clinical practice for starting and
calibration of the cochlear implant by the audiologist) and a speech processor Cochlear
Freedom (delivered consignment for the study) the implanted device (receiver-stimulator) in
patient surgery.
With this software data electrode impedance will be obtained twice a day, in different
configurations stimulation and measurement, and will be sent automatically via Internet to a
remote server managed by the authors of this protocol.
Postoperative controls on floor and then not differ outpatient than usual for these
procedures.
Blind:blind will be maintained for this study the researcher, the patient, evaluation of
results and analysts. The only not blind will be who prepares the medication from pharmacy.
Electrical impedance measurements are automatic and blind although objective measurements are
discussed.
Blind opening procedure:opening blind held immediately in the event of occurrence of an intra
or postoperative complication (eg intraoperative hemodynamic alteration, uncontrollable
bleeding, infection, fever, allergic reaction, wound dehiscence). Similarly, the blind will
be opened for the group of principal investigators, always after completing the stage of
implementation of the protocol in patients in question, and each not less than 2 months and
the sole purpose of making a partial analysis the results that may involve changing the
acquisition parameters of samples for a better interpretation of the results and to fulfill
the main objective stipulated.
Place work Patients will be evaluated at the Department of Otolaryngology, Hospital Italiano
de Buenos Aires as usual in this type of evaluation. Surgery is carried out in the central
operating room of the hospital by any of the three surgeons otologists privileges for these
procedures and not differ from the usual surgical technique for cochlear implantation. THe
postsurgical controls will be performed in the same service by the same professionals.
Measurements of proposals impedances are performed for the oun paciente or his parents, using
the same technique and the same equipment used by Audiologists in visits calibration cochlear
implants, with help of software designed by researchers specifically for this purpose. The
data will be transferred remotely through a security protocol to a fund administered by the
principal investigators (cloud) server. Further analysis of the data, evaluation of the
results and conclusions of the work will be performed by the principal investigators of this
protocol in the field of Hospital Italiano de Buenos Aires.
Population All cochlear implant candidates who meet all inclusion criteria and no exclusion
criteria patients and to accept participation in the protocol will be recruited.
Note: If a patient is candidate for bilateral cochlear implant or for the duration of the
study is candidate for reimplantation each ear will be considered separately. In this case
each ear will be randomized separately following the same procedure.
Definitions Gusher:outpour of perilinfa before the surgical opening of the inner ear.
Minimally traumatic cochlear implant surgery:surgical procedure for placing an electronic
implantable device to partially restore hearing function in patients diagnosed with severe
sensorineural hearing loss to profound unilateral or bilateral that do not respond to other
forms of hearing rehabilitation and meet medical, audiological, radiological and
psychological criteria for cochlear implantation.
Minimally traumatic surgical technique consisting placing the receiver-stimulator implant
beneath the skin on the temporo-parietal region and an array of electrodes that must be
positioned in the scala tympani of the cochlea, not generating any damage to structures level
the outer and middle ear (tympanic membrane, middle ear bones) as well as minimum damage to
the delicate microstructures inner ear, avoiding maneuvers abrupt opening of the inner ear,
suction labyrinthine liquid inlet bone powder or blood the cochlea, and allowing the
introduction of the electrode array into the cochlea very slowly, in the direction with
better orientation and parallel basal turn the scala tympani.
To do this, the procedure is performed under general anesthesia through a small incision,
extending from the tip of the mastoid to temporo-parietal region. It said incision includes
the skin, subcutaneous tissue, muscle and periosteum in the same line. A small
postero-superior subperiosteal pocket where it will be hosted the receiver-stimulator implant
is then generated; for which bone cutter in a small bowl of about 2 cm in diameter. Then a
simple mastoidectomy is performed, exposing and preserving the anvil and the approach is
completed with a posterior tympanotomy or approach to facial recess under monitoring of the
facial nerve and preserving the structure. Ideally it identifies and preserves cord tympani
nerve (anterior posterior limit of the tympanostomy). Through the latter the tympanic box is
displayed and the round window niche (anatomical repair in relation to the scala tympani of
the cochlea) is identified. Careful hemostasis is performed and the mucosa of the margins of
the round window DeCola. Usually at this point is necessary and milling at low speed gently
and above upper lip of said recess to allow better visualization of the round window membrane
(eardrum side). At this point,is necessary for a thorough washing of entire surgical area in
order to clear debris or blood bone powder. Then isotonic saline (SF group) or dexamethasone
(DEX group) in the tympanic cavity through the posterior tympanotomy, taking special care to
the round window membrane is completely submerged in the liquid instill. The implantable
device (cochlear implant) is then placed and secured by a suture. At this time it will
proceed to the delicate opening of the membranous labyrinth, either through the round window
itself, through a small anterior and lower extension thereof or through a cochleostomy
(anterior and inferior bone milling margins the round window), performing the endosteal and
carefully opening the membranous labyrinth, with special emphasis on not allow entry of bone
dust or blood, as well as preventing aspiration of labyrinthine fluid (perilymph). It shall
then be slow and progressive introduction of the array of electrodes, with the technique
described by the manufacturer as the electrode toused, CI512, CI522 and CI532, progressing
the array in the right direction (tangential to the direction of the scala tympani at level
of the basal turn of the cochlea) until the entire array of electrodes is positioned within
the cochlea. To be completed by sealing the edges of the round window with a small piece of
muscle, bone powder level back tympanostomy and finally rearranged the remaining wires in the
mastoid cavity, avoiding excessive mobilization, fixing them with a piece of gel foam inside
it. The layered closure, periosteum, muscle-fatty cellular and skin absorbable suture is
completed. A local flat cure furacinada gauze and a bandage is made. He shall carry out the
routine tests and neural response telemetry. End of the surgical procedure.
Intervention Patients admitted with diagnosis of severe sensorineural hearing loss or
profound unilateral or bilateral that are evaluated and meet the criteria for candidacy for
cochlear implant and comply turn all the inclusion criteria and none of exclusion, will be
invited to participate in the study.
Accepted this, a randomized double blind study where the pharmacy is responsible for
randomizing treatment among participants proposed subjects. Each of these activities will be
properly recorded in writing.
Then they are subjected to usual for placement cochlear implant according the technique of
minimally traumatic cochlear implant surgery and used worldwide spread surgery. Reached the
operating time in which the round window is displayed (reference anatomical structure of the
inner ear and where (or margins) cochlear implant is usually introduced) will proceed as
follows, identical in both groups Experimental (DEX) topical dexamethasone (Decadron shock
are placed® laboratory Sidus)in concentration of 20mg / ml in single dose in the eardrum of
the middle ear through posterior tympanostomy during cochlear implant surgery, taking special
care that the membrane round window is completely submerged in the liquid, prior to insertion
of the array of electrodes.
Placebo group (SF):
physiologic solution is placed isotonic sterile single dose in the eardrum of the middle ear
through posterior tympanostomy during cochlear implant surgery, taking special care that the
membrane of the round window is completely submerged in the liquid, prior to insertion of the
array of electrodes.
Pharmacy Hospital Italiano de Buenos Aires will be responsible for providing the drug and
placebo. It handle it, receiving, contabilizándola, storing and delivering relieving against
medical prescription. It will ensure that it is used solely for the purposes of the study.
Each of the activities will be recorded in writing. Pharmacy Hospital Italiano de Buenos
Aires (HIBA) is the only non blind study participant.
After the surgical procedure, the patient remain hospitalized 24 hours as usual in this type
of procedure. Finally cures and weekly inspections shall be made during the first month until
activation of the implantable device and continue audiological rehabilitation therapy.
From the day of surgery including, until day programmed for activating the implant, all
patients enrolled the study (2 intervening groups) made identically and by themselves or by
the help of a relative or guardian, measurements daily (morning and evening) of the
impedances of the electrodes of the implant with the CIDC software (available free the day of
surgery) and the communication interface POD through a speech processor Cochlear Freedom
delivered on consignment during tests for such end.
The result of the measurements of each patient will be sent automatically and as soon as
become available internet connection, from the patient's own computer to a remote server
(cloud) administered by researchers.
The study ends on the final activation of cochlear implant (approximately 30 days after
surgery), at which the implant is permanently connected by the audiologist to your speech
processor and the items delivered on consignment for the study will be returned (POD
communication interface and speech processor Cochlear Freedom).
Sampling and sample calculation All patients who meet the inclusion criteria and no exclusion
to participate in the study and these will be distributed in a randomized into one of two
treatment arms will be invited. Monitoring each patient shall be performed within 30 days; it
coincides with the usual postoperative controls first week and first postoperative month.
The cochlea with fibrosis exhibit electrical impedance at about 20 KQ compared to a normal
cochlea at the day of implant activation (approximately 30 days) 7 KQ with a common standard
deviation of 1,481KΩ. To test the null hypothesis that the impedance is equal in patients who
were administered steroids and those not were applied, with a power of 80% and an alpha of 5%
to test two tailed required 10 patients per group.
With the sample size reached 4980 capacitance values are obtained per patient (20 patients,
with 22 electrodes each evaluated in four sequences impedances, with two daily measurements
for 30 days). This sample size achieved in 10 patients per group is sufficient for the
purpose of describing the behavior of the capacitive impedance component with and without
corticosteroid over time.
The sample calculation was performed using STATA 14.0 software and Power and Precision
version 4.
Implementation of the clinical
The protocol is conducted in two stages:
Stage 1: Validation "in silico" software to measure impedances. In order to obtain the
samples needed to analyze and meet the objectives in this protocol, it is required perform in
the patient impedances measurements through the implanted recent device. This is done
conventionally in the clinic, by transient connecting a measuring coil which is coupled to
implantable device, and through communication interface is integrated to a computer (in the
same way that the audiologist makes calibrations sessions on and calibration). By suitable
software, measurements can be obtained. However, given the cumbersome and likely poor
adhesion to it if you consider that the patient must attend twice a day to treating facility
during the first postoperative to make the necessary measurements month, the group of leading
researchers this protocol devised and developed their own software that allows a safe,
outpatient basis, and the patient's home, taking measurements by himself. In turn, the
software in question should allow to measure with the stipulated parameters and the set
sequences. The software, called "Cochlear Implant Data Collector (CIDC)" was developed
specifically for the realization of this work (and possibly future) and validated by the
authors. It is intended to be distributed for free, and installed on the computer from the
patient to make measurements. Details thereof, its operation, validation and security are
further described in Annex 3.
Step 2: Patient inclusion. Surgery. Impedance measurement Inclusion of patients:Patients who
are candidates for cochlear implantation unilateral or bilateral and that meet the selection
criteria (see inclusion / exclusion). They explained the protocol and will be asked sign
informed consent. It will notify the Hospital Italiano central pharmacy to incorporate the
patient randomization and drug preparation / matching placebo for the day of surgery.
Surgical procedure will proceed to the cochlear implant surgery according the conventionally
accepted worldwide and known as classic description minimally traumatic cochlear implant
surgery (see definitions section). As soon as the access to the tympanic cavity is achieved
through the posterior tympanostomy and have identified the round window, proceed according
the group randomized to placement or otherwise of the corresponding substance, instilling it
directly through the posterior tympanotomy, to completely fill the tympanic cavity, taking
special care that the secondary eardrum round window is immersed therein. Then continue with
the milling of the bowl to the receiver-stimulator, a cochlear implant is placed in the bed,
and slowly and continuously inserting the array of electrodes, either round window round
window extended or cochleostomy in ramp will tympanic, according surgeon preference and
judgment to meet the primary objective of minimally invasive approach controlling the
insertion time in seconds. Finally closing the surgery is completed until completion. It
shall then be measuring impedances and neural response as is customary in this procedure.
Measurements using Software "Cochlear Implant Data Collector":out to bring the proposed
objective of this study analysis was designed and validated "CIDC" software (see Appendix 3),
whereby the patient perform every 12 hs about measurements of the impedances of the
electrodes in the sequence routine and established for this purpose in the software.
Sequences stimulation and measurement are as follows:
Sequence1:this sequence involves the monopolar stimulation of each of the 22 intracochlear
electrodes as cathode, with the two extracochlear electrodes reference: "Monopolar 1 + 2"
(MP1 + 2) Mode (anode). During each stimulation was recorded by measuring the voltage
obtained from the same electrode stimulated and reference electrodes in the 14 available time
slots by the chipset cic4 implant. Thus 308 samples will be obtained.
Sequence2:Mode "common ground" (CG): this sequence involves stimulation of each of the
individual electrodes 22 as cathode, with reference (anode) to the rest of the array of
electrodes. During each stimulation was recorded by measuring the voltage obtained between
the same electrode and the remaining stimulated intracochlear electrodes in the 14 available
time slots by the chipset cic4 implant. Thus 308 samples will be obtained.
Sequence3:Mode "3 points" (3P): intracochlear electrodes will be stimulated sequentially from
1 to 20 inclusive using the following logic: cathode electrode = 'n'; anode electrode = 'n +
2'. Voltage between electrodes nn + 1 is recorded simultaneously at the 14 available time
slots by the chipset cic4 implant. Thus 280 samples will be obtained.
Sequence4:Mode "4 points" (4P): intracochlear electrodes stimulate sequentially 1 to 19
inclusive using the following logic: cathode electrode = 'n'; anode electrode = 'n + 3'. The
voltage between electrodes n + 1 and n + 2 in the 14 available time slots by the chipset
implant cic4 be recorded simultaneously. Thus 266 samples will be obtained.
In each sequence described above is used as stimulation parameters constant the following
values:
current level: 80 units of current (corresponding the data sheet chipset cic4 to 74.21 uA)
Time between phases: 8 mS Period: 333.4 mS Pulse width : two sequences, 25 and 50 mS
All the sequences described above are made using two different pulse widths predetermined
stimulation 25 and 50 mS.
To make these measurements, the company Cochlear LTD or his representative in the country
(Tecnosalud SA) provided no cost, a Freedom ™ and an interface POD to connect to computer
from the patient, where it install the software processor with a single executable
distributed the day of surgery in a pendrive with the appropriate language (Spanish, English,
German, Portuguese). All devices will be provided on loan for development work and will be
returned to medical team on the day,date on which end data by the patient.
All measured by the software and the context information values (especially the parameters
used for each individual measurement and time) are stored in a local database. From the time
the application performs periodic attempts to export the data to a database located on a
server in the cloud. This database is capable of centralizing measurements unlimited
patients. The server is managed and maintained by the principal investigators of this
protocol.
Statistical analysis The analysis will be performed by protocol and by intention to treat.
The analysis unit be each patient into one of two treatment arms.
Descriptive analysis of quantitative variables with mean and standard deviation or median and
interquartile range as observed distribution is expressed. Categorical variables are
expressed in proportion to confidence interval for the ratio.
The effect of corticosteroid (dexamethasone) on the variable impedance and capacitance
results with generalized equation estimated (GEE) measured. The natural grouping of the
individual measurements and the times (panel data) are considered.
Statistical analysis was performed using STATA version 14.0 software. They are considered
statistically significant lower probability to 5%.
Clinical management and neglect each patient autonomy be respected to discontinue treatment
at any time by communicating to researchers.If the medical staff, researchers or the patient
believe that the individual is at risk because the trial, the same will be withdrawn from the
study and will explain the reasons why that decision is taken.
Adverse events Adverse events were collected for each control and each time the patient
contact the investigator. They are classified according the scale described by Dindo
complications and Clavien in 2004 [24,25].Complications are described as deviations from
normal postoperative, not including the consequences inherent the procedure itself.
Complications grades are:
Grade 0: no complications Grade I: Any deviation from the normal postoperative course that
does not require pharmacological, surgical or endoscopic treatment and does not require
radiological interventions. It included in this level using antinauseants, antipyretics,
analgesics, diuretics, electrolytes and physiotherapy, as well as drainage of wound
infections "bedside".
Grade II: Requires pharmacological treatment with drugs not included in the grade, including
transfusions and parenteral nutrition.
Grade III: require surgical, endoscopic or radiological intervention treatment:
IIIa:without general IIIb: anesthesia:general anesthesia Grade IV: life-threatening
complication requiring handling unit closed. IVa: Dysfunction of a single body IVb:
multiorgan dysfunction Grade V: patient death Damage or complications While complications or
damage caused by single topical application of dexamethasone on the round window in single
dose during surgery cochlear implant or performing in routine and systematic measurements of
the impedances of the electrodes with the proposals and designed in the CIDC software as well
as the procedure carried out for measuring them is estimated at zero or extremely rare
sequences, the costs of any complications or damages related to procedures or treatments of
the study will be funded by the Department of Otolaryngology, Hospital Italiano de Buenos
Aires.
Ethical considerations This protocol is drawn and carried in accordance with current national
and international standards: Declaration of Helsinki of the World Medical Association,
Disposition ANMAT 6770/10 and the Guidelines for Good Clinical Practice ICH E6.
The trial protocol, the patient information and informed consent forms will be submitted to
evaluation committee of research projects Hospital Italiano de Buenos Aires (HIBA) (CEPI) for
possible approval.
In all cases, the participation of the study is voluntary and certified by the process of
informed consent.
The right to opt be respected at all times in the studio without implying in any way any
discrimination, differential treatment or abuse without mediate any implication in the
treatment of the patient's disease.
Any patient wishing leave the research protocol will be automatically removed from the
protocol and not considered for the interpretation of results.
Diagnostic evaluation, surgical procedure, as well as the type, make and model of implantable
device used not differ in any way or manner to what is practiced or used routinely in our
institution regularly.
All data collected will be treated confidentially and anonymously. Only authorized personnel
can access records of study according to the current legal regulation: National Personal
Information Protection Law No. 25,326 (Law of Habeas Data).
All patients will be informed of the study objectives; possible adverse events; the
procedures; the potential risks they face and; the treatment allocation mechanism.
Moreover,is the researcher's responsibility explain to patients their roles in the trial. You
will be informed about the strict confidentiality of your personal data, but your medical
records may be reviewed for trial purposes by authorized other than your treating physician
individuals.
The test results will be stored in accordance with the law of local data protection / ICH GCP
- Guidelines and will be treated with utmost confidentiality.
