Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01847937 |
| Other study ID # |
1-10-72-85-13 |
| Secondary ID |
VEK: 1-10-72-85- |
| Status |
Completed |
| Phase |
N/A
|
| First received |
April 12, 2013 |
| Last updated |
February 2, 2017 |
| Start date |
May 2013 |
| Est. completion date |
September 2016 |
Study information
| Verified date |
February 2017 |
| Source |
Aarhus University Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This project aims to develop high field MR techniques to detect nerve lesions in diabetic
patients. The MRI findings will be compared to results from conventional evaluations and
nerve conduction studies to determine the validity as part of a clinical practice.
Description:
Background
Diabetes mellitus is a very frequent disorder with an estimated prevalence of 275,000
patients in Denmark. Diabetic peripheral neuropathy (DPN) is a late complication which often
remains undiagnosed, but may occur in up to 40% of diabetic patients. Advanced neuropathy
may induce irreversible damages to the nervous tissue, and to avoid further damages, early
diagnosis is important followed by optimal treatment of diabetes. DPN is a common
complication due to long term diabetes in both type 1 and type 2.
Nerve conduction studies (NCS) is the gold standard method to diagnose DPN. However, the
technique is time consuming and introduces discomfort to the patient and, furthermore, early
nerve dysfunction may not be detected by NCS. Magnetic resonance imaging (MRI) (3 Tesla) of
peripheral nerves is a new technique entitled Magnetic resonance neurography (MRN). In
recent studies MRN has documented morphological changes in individual nerve fascicles. In
T2-weighted images hyperintensity is present in proximal parts of nerves from neuropathic
patients as compared to healthy nerves. This hyperintensity is believed to reflect early and
more widespread lesions to the nerve fascicles that are not detected by NCS. This is
pointing towards MRN to become an important tool in the management of patient with
peripheral neuropathies.
Recent technical development such as diffusion weighted imaging (DWI) and diffusion tensor
imaging (DTI) are currently being evaluated for imaging of the peripheral nerve system. DTI
is expected to provide information about the physiology of the nerves and may reveal
vascular congestion such as; blockade of axoplasmic flow, leading to abnormal proximal
accumulation of endoneurial fluid; and distal Wallerian degeneration changes. Fiber tracking
used on DTI is clinically implemented in some cases of stroke, tumours, neuropathy surgery,
and functional brain MR imaging. Additionally, fiber tracking has been used on neuropathic
patients with carpal tunnel syndrome, but has yet to be used in DPN as a measure of
physiological function of the peripheral nerves.
Investigator, sponsor and trail setting Patients will be recruited at Department of
Endocrinology and Internal Medicine from a cohort of more than 1000 well-characterized
diabetic patients. The main investigator finished his masters as a biomedical engineer at
the MR Centre at Aarhus University Hospital where he specialized in MR scanning techniques
and has since been working with research combining diabetes, neuropathy, MR techniques and
image processing. The studies will be conducted in collaboration between Siemens AG,
Copenhagen, Department of Endocrinology and Internal Medicine, Department of Neurology, MR
Centre at Aarhus University Hospital, Department of Endocrinology and Internal Medicine at
Odense University Hospital and Department of Neuroradiology at Heidelberg University
Hospital.
The main researchers on the project are as follows:
Main Investigator Michael Vaeggemose, MSc, Biomedical Engineering Department of Neurology,
Aarhus University Hospital, Denmark
Supervisor Henning Andersen Professor, MD, PhD, Neurologist Department of Neurology, Aarhus
University Hospital, Denmark
Supervisor Niels Ejskjaer Associate Professor, MD, PhD, Endocrinologist Department of
Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark
Supervisor Knud Yderstraede Associate Professor, MD, PhD, Endocrinologist Department of
Endocrinology, Odense University Hospital, Denmark
Supervisor Steffen Ringgaard Associate Professor, PhD, MR Physicist The MR Centre, Aarhus
University Hospital, Denmark
Objective
This project aims to develop high field MR techniques to detect nerve lesions in diabetic
patients. The MRI findings will be compared to results from conventional evaluations and
nerve conduction studies to determine the validity as part of a clinical practice.
Methods
Blood sample
For the diagnosis of diabetes, HbA1c is used. This is the measure of how much glucose
binding to hemoglobin in the blood. Diabetics have a higher blood sugar levels than healthy,
there is definitely a threshold for diabetes that are at glucose values exceeding 64mmol/mol
(8%). HbA1c is determined from a blood sample.
Clinical neurological test
Diabetics with and without neuropathy, hereditary axonal and demyelinated nerve injury
patients examined with a clinical neurological test of sensibility, muscle power and
reflexes. Examination of reflexes in the arms and legs performed with reflex hammer while
the assessment of muscle strength is performed by trial participants to stretch and bend the
arms and legs during resistance from the examiner. The subjects' sensibility of the soles is
tested with a cotton swab and test participant shall so indicate on the touch can be felt.
Furthermore the trial participants' vibration sensitivity of the soles is tested with a
tuning fork. There is a possibly that the test of the muscles subsequently lead to slight
muscle soreness, but otherwise there will be no significant risks, side effects or
discomfort associated with the clinical neurological testing.
Neurophysiological studies
The neurophysiological studies include electroneurography (ENG) and Motor Unit Number
Estimate (MUNE) and Motor Unit Number Index (MUNIX). The neurophysiological studies
performed at the Clinical Neurophysiology Department, Aarhus University Hospital using
EMG-equipped Keypoint (Medtronic, Skovlunde, Denmark).
Electroneurography (Nerve conduction study)
Nerve conduction studies are performed with the department's standardized methods and
include:
1. Motor nerve conduction study and F-waves with surface electrodes on the ulnar peroneus,
bilateral and tibial nerve, bilaterally.
2. Sensory nerve conduction study with surface electrodes of the sural nerve, bilaterally.
Nerve conduction velocities, amplitudes of the sensory and motor potential, distal motor
latencies and minimum F-wave latencies are the parameters to be evaluated with nerve
conduction studies.
MUNE Multipoint Stimulation & MUNIX
Motor Unit Number Estimate (MUNE) provides information on the number of functioning motor
units in the studied muscle. The estimate is based on the ratio of the maximum Compound
Muscle Action Potential (CMAP) and an average of that muscle on Surface Motor Unit
Potentials (SMUP). In the current study used Multipoint Stimulation (MPS) for the
stimulation of a nerve of one lower limb and a nerve in one upper limb per. participant.
There is a one supramaximal nerve stimulation whereby the maximum CMAP determined with
surface electrodes.
Then the nerve is stimulated, starting from 0 mA and increasing intensity to the first
all-or-nothing SMUP observed. The intensity varied further until the measured SMUP not show
variation (alternation.) process is carried out by moving the electrode a few millimetres
along the nerve. This is done until a representative number SMUP is measured approx. 10 per.
nerve.
Motor Unit Number Index (MUNIX) is also a MUNE technique. There will be conducted one
supramaximal nerve stimulation with surface electrodes to obtain CMAP in the same nerve as
used above. The next stage is electromyography (EMG) with the inclusion of surface
interference pattern in voluntary contraction, typically by 10 different contractions
between 10% and 90% of maximal contraction force.
The neurophysiological studies (ENG, MUNE, MUNIX) takes a total of 2 hours per trial
participant and performed at the bonded small surface electrodes, respectively in hands or
feet.
Muscle potential and nerve potential recorded through these surface electrodes for
stimulation of the nerve with brief surges through the skin. This feels like a beating or
pressing in the skin and may be associated with mild discomfort. Otherwise, the studies are
not associated with any kind of risk or side effects.
MR Neurography (MRN)
MRN study will be conducted at Magnetrom Skyra 3 Tesla MR scanner (Siemens AG, Erlangen,
Germany), which is set up to perform a MRN protocol with the following 5 sequences.
1. DIXON
2. Spectral adiabatic inversion recovery (SPAIR)
3. Short tau inversion recovery (STIR)
4. T2-weighted turbo spin echo (T2 TSE)
5. Diffusion weighted imaging (DWI)
Before the scan test, the subject must complete and comply with the rules of MRI safety. A
description of the MRI scanning process, alarm ball, and a description of the noises the
scanner produces is described to the subject. MRI methods for visualization of nerves does
not use contrast agents, which is advantageous in the study of diabetes patients who may
have reduced kidney function. The subject is placed supine on a bed with legs towards the
scanner. To minimize motion artefacts a light fixation of the lower leg with foam pads is
used. Around the foam pads and lower extremities is a 16-channel Peripheral Angio Array coil
(Siemens AG, Erlangen, Germany) or multiple 18-channel Body Matrix coils (Siemens AG,
Erlangen, Germany) located. To avoid hearing damage is a hearing protector placed on the
subject's ear. If problems occur the test subject can at any time squeeze the alarm ball
which is located in one hand, with a pressure on it and a direct contact with the
investigator will be created and the patient can be moved out of the scanner. The scanning
process is expected to take 2 hours with changing cloth, instruction and scanning. MRI scans
are not associated with any kind of risk or side effects.
Quantitative sensory testing
Quantitative sensory testing (QST) is used to determine vibration threshold via a
computerized sensory evaluation system (CASE IV WR Medical Electronics, Stillwater, MN,
USA). This study investigated the trial participants' ability to perceive vibrations caused
respectively the dominant index finger and the non-dominant foot big toe. In addition,
temperature variation and pain perception in unity describes the neurological affliction
stage and scope. The test is evaluated to exceeding patient specific thresholds for normal
sensitivity or the extent of the patient's reduced or exaggerated sensitivity. The thermal
test is an electrode applied to the skin. By adjusting the voltage of the electrode modified
heat of the electrode with a linear increasing or decreasing the development of 40 degrees
per second. Meanwhile the patient will be asked if he feel a temperature discomfort. QST is
not associated with side effects, risks or discomfort.
Isokinetic dynamometry
The trail subjects' muscular strength is determined by isokinetic dynamometry. The test
measures the maximum isokinetic strength of the shoulder flexor and extensor muscles of the
dominant arm and the ankle flexor and extensor muscles in the non-dominant leg. Trials
participant contract the muscles one at a time during a resistance and the study consists of
a maximum of eight repetitions. This is done with a Biodex System 3 PRO dynamometer (Biodex
Medical Systems Inc. NY, USA) and follows a standardized protocol. In very rare cases,
muscle strain and tendinitis (less than 2 ‰) may occur, further risk, side effects or
discomfort is not associated with the use of isokinetic dynamometry.
Statistical considerations
Comparison between matched groups will be performed using conventional statistic methods
unpaired t-test or non-parametric tests such as Wilcoxon signed-rank test. In variation
analyses of several groups ANOVA and ANCOVA will be used. A significant difference of
p-values below 0.05 has to be determined, to determine the validity of the findings.
Comparing the conventional methods to the MRI method from the binary outcome of being
healthy or suffer from DPN, given an estimated sensitivity of 1 and a Specificity of 0.7,
makes it possible to determine the required sample size. From a McNemar's test with a
significant level of 5% a power calculation were performed giving a needed sample size of at
least 50 subjects (healthy and diabetic with and without neuropathy). Inclusion of patients
with axonal and demyelinated nerve lesions, to compare the resemblance of solely axonal and
demyelinated damage to diabetic peripheral neuropathy, is in its current numbers not based
on a statistical power calculation.
Volunteers
The trail consists of patients with type I and type II diabetes, with and without
neuropathy. Patients will be recruited at the Department of Endocrinology, Noerrebrogade 44,
Aarhus University Hospital. Patients with hereditary axonal and demyelinated neuropathy will
be included at the Department of Neurology, Noerrebrogade 44, Aarhus University Hospital.
Healthy subjects will be recruited through public media. In the 3 year course of the study
it is expected to include 90 diabetics with and without neuropathy, 10 patients with
hereditary axonal neuropathy and 10 patients with demyelinated neuropathy, as well as 35
healthy control subjects. This amounts to a total of 145 subjects.
Side effects, risk and disadvantages
The clinic neurological examinations test the subjects' reflexes, muscle strength and
sensibility. The test of muscle strength can cause light muscle aches, but otherwise there
will be no significant risks, side effects or disadvantages connected to the clinic
neurological tests.
Vibration threshold is determined through a computer based sensory evaluation system (CASE
IV, WE Medical Electronics, Stilwater, MN, USA) and is not connected to significant risks,
side effects or disadvantages.
For examination of muscle strength the Biodex System 3 PRO dynamometer (Biodex Medical
Systems Inc. NY, USA) is used. I very rare cases muscle strain and tendonitis (less than 2
‰) I connection to the examination, otherwise there will be no significant risks, side
effects or disadvantages connected to tests.
The neurophysiological examinations (ENG, MUNE, and MUNIX) are performed with surface
electrodes with short bursts of electrical current through the skin. It feels like a beating
or pressing under or in the skin and can be connected to discomfort. Besides this the tests
are not connected to significant risks, side effects or disadvantages.
MR scans is not connected to any known risks and the patients ears will be protected with
soundproofing earplugs or headphones to avoid the discomfort in relation to the high sound
the scanner makes during the scans. The patients head will be placed outside the scanner,
with the legs in the scanner, removing the risk of making the patient feel claustrophobic.
The blood test can be connected to slight discomfort and a small risk of developing
accumulation of blood and infection at the needle injection site. If any sign of infection
(rash, heating, tenderness, swelling) the subject must seek the investigator or the
emergency room. Det combined blood loss in connection to the blood test will not exceed
250ml, which is a lot less than a blood donation includes.
The blood test is analysed and destroyed after. A bio bank will not be established in this
project.
Since there's no significant side effects and risks in participating in the project it is
considered that the project is scientific ethically justifiable.
Economic conditions
Expenses in connection to the project are covered by the involved departments. The
researchers have no economic conflict of interest in the project. Transport expenses in
connection to oral information and examination is refunded in regard to the guidelines used
at the departments. In regard to national guidelines the subjects will be paid compensation
for their partition in the project.
Publication of results
The results will be published in a recognized international paper in account to the
Vancouver regulations regardless of the results are positive, negative or inconclusive.
Do the subjects wish information about the project results they can inform the investigator
and he will send the information to the interested subjects.
National ethical committee review
The project is reported and approved by the Danish Data Protection Agency, Danish National
Committee on Health Research Ethics (nr. 1-10-72-85-13) and the department legislations.
Volunteer recruitment
Subjects with peripheral nerve disease and non-neuropathic diabetic patients are recruited
in the clinic at the Department of Neurology and Medical Department of Endocrinology, Aarhus
University Hospital. Relevant potential subjects will be identified through their planned
visit to Neurological clinic or Endocrinology clinic. Potential subjects (healthy controls,
diabetics and patients with peripheral nerve disease) will receive written information about
the research project with a request to contact the main investigator Michael Vaeggemose per
letter, e-mail or telephone if they want further information about the research project.
Healthy control subjects will be recruited by posting information material on public
bulletin boards and in the local newspaper, indicating the main investigators phone number
and e-mail address. Potential volunteers who want further information about the project
would then subsequently receive the written participant information and National Ethics
Committees information in regard to participating in a health science research project, and
call for an information interview. The potential subject has the opportunity to bring a
companion to the information interview and is informed of the right to stop participating in
the project is he/she chooses to.
The information interview is conducted by PhD students, MSc biomedical engineer, Michael
Vaeggemose who with in depth knowledge and close association to the studio has the necessary
academic qualifications to do so. The conversation held in a conference room in undisturbed
environment at Aarhus University Hospital, where the potential trial participant has the
opportunity to bring a companion. Indicated during the interview that there is a request for
participation in a biomedical research project and given an oral understandable presentation
of the research project without using technical terms. During the interview, there will be
enough time for the subject to listen to the oral information and ask questions. The
conversation adapted beneficiary's individual requirements in terms of experience, maturity,
age, etc.. The interview will be based on the written participant information and will
include any foreseeable risks, side effects, complications and inconveniences associated
with participation in the research project and that there may be unforeseen risks and
impacts associated with participation in the research project. Furthermore, it is stated
that information about health conditions, purely private matters and other confidential
information may be disclosed to and processed by persons responsible for carrying out a
statutory quality of the study. The subject is informed also about the right to decline
knowledge of new essential health data in the project.
After information interview the potential trial participants has at least 1 week to think
before signing the consent form. The subjects may at any time without consequences withdraw
from the research project. It is desired to gain access to patient records, as evidenced by
the written patient information. After the information interview the participant will be
informed if, during the completion of the study, new data on the risks, complications and
disadvantages in the trials has changed significantly in regard to the subject's safety. In
the event that the study show crucial information about the subject's state of health it
will be disclosed to the individual trial participant, unless they unequivocally expressed
that this is not desired. The subjects will be informed of the results and of any
consequences for the individual. There will be, upon completion of the project, a short easy
to understand report in Danish summarizing the project's main results, as the individual
trial participant may obtain by contacting the projects main investigator (Michael
Vaeggemose). If the research project is interrupted the trial participants will be notified
of the reason for this.
