The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial registered on ANZCTR


Registration number
ACTRN12617000034336
Ethics application status
Approved
Date submitted
3/01/2017
Date registered
9/01/2017
Date last updated
29/01/2019
Date data sharing statement initially provided
29/01/2019
Date results information initially provided
29/01/2019
Type of registration
Prospectively registered

Titles & IDs
Public title
An investigation into the effect of skin stimulation on smell function
Scientific title
An investigation for the modulation of Olfactory (Smell) function using Non-Invasive Transcutaneous Electrical Nerve Stimulation in healthy adult male volunteers
Secondary ID [1] 290830 0
None
Universal Trial Number (UTN)
U1111-1191-3010
Trial acronym
MODOLF
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Alzheimer disease 301504 0
Parkinson's Disease 301535 0
Dementia 301536 0
Appetite disorders 301537 0
Condition category
Condition code
Neurological 301214 301214 0 0
Alzheimer's disease
Neurological 301255 301255 0 0
Parkinson's disease
Neurological 301256 301256 0 0
Dementias

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Transcutaneous Electrical Nerve Stimulation (TENS) will be applied under the pain threshold with CE approved home use TENS device by a researcher who is a medical doctor.
Different dilutions of smell sticks (scientifically validated and medically approved) will be used to determine the smell function of the participants before and after the TENS interventions by an odour researcher. The number of the smell sticks that will be used may differ 4 to 10 because of the interindividual smell threshold differences.
In all sessions, frontal cortex activation will be monitored for olfactory function responses with FDA approved near infrared monitoring device (NIRS). In each arm, there will be two streams: low(10Hz) and high frequency(80Hz) stimulation. 24 participants of each Arm will be allocated into two streams: 12 participants for low frequency stimulation stream and the other 12 participants for high frequency stimulation stream. Each stream will also have their own placebo group in which the same 12 participants will be enrolled. There is no evidence that 10 minutes of a single stimulation have prolonged effects. In addition, each session will be performed on a different day(active or placebo) so that the participants will be participating in different days for each session to eliminate the possible overlapping effects of the previous session. Each session duration will take 1 hour (baseline tests+stimulation+after stimulation tests) and each participant will be participating for a total of 2 hours in two different days(one day for active and one day for placebo session). All sessions will take place in the live human research/ultrasound room in Otago University, Department of Anatomy, Dunedin.
Arm1 : TENS will be applied to ear skin(direct vagus nerve stimulation) with ear specific TENS electrode under pain threshold to 24 healthy volunteers for 10 minutes. This is a within designed study, therefore each participant will be participating both to an active and a placebo. 12 of the participants will be allocated to low frequency active stimulation stream and the other 12 of the participants will be allocated to high frequency active stimulation stream.Each stream will also have their own placebo group in which the same 12 participants will be enrolled.
Arm2: TENS will be applied to wrist skin(indirect vagus nerve stimulation) with body specific TENS electrode under pain threshold to 24 healthy volunteers for 10 minutes. This is a within designed study, therefore each participant will be participating both to active and placebo groups. 12 of the participants will be allocated to low frequency active stimulation stream and the other 12 of the participants will be allocated to high frequency active stimulation stream. Each stream will also have their own placebo group in which the same 12 participants will be enrolled.
Intervention code [1] 296751 0
Treatment: Devices
Comparator / control treatment
This is a within study on healthy volunteers. Each participant will be enrolled to both active and placebo control groups. In the placebo control group, the TENS electrodes will be placed on the same skin areas for 10 minutes as in the active group but there won't be an electrostimulation.
Control group
Placebo

Outcomes
Primary outcome [1] 300627 0
Change in Sniff-stick threshold test results (statistical difference in detection odours based on detection of the same odour after the electrostimulation).
Timepoint [1] 300627 0
before and after 10 minutes of Transcutaneous Electrical Nerve Stimulation or 10 minutes of Placebo session
Secondary outcome [1] 330438 0
% Change in Near Infrared Monitoring score of Frontal Cortex perfusion
Timepoint [1] 330438 0
before and after 10 minutes of Transcutaneous Electrical Nerve Stimulation or 10 minutes of Placebo session

Eligibility
Key inclusion criteria
* 22-39 years old male
* NZ European
* In good health, and not on any regular medication
* A non-smoker
Minimum age
20 Years
Maximum age
39 Years
Gender
Males
Can healthy volunteers participate?
Yes
Key exclusion criteria
Have a history of allergies, any neurological disorder, cardiac disease or are on regular medication

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
numbered containers
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s

The people assessing the outcomes
Intervention assignment
Crossover
Other design features
Within design (same participants will be enrolled both active and placebo groups).
Phase
Phase 1
Type of endpoint(s)
Efficacy
Statistical methods / analysis
There was no similar(non-invasive olfactory neuromodulation) study in humans. Therefore the minimum number of participants(n=48) was estimated on the basis of other non-invasive nerve stimulation study designs in humans. In addition, within design is preferred to improve the potential power of the study. T-test will be used to analyze the results.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 8540 0
New Zealand
State/province [1] 8540 0
OTAGO

Funding & Sponsors
Funding source category [1] 295254 0
University
Name [1] 295254 0
Otago University
Address [1] 295254 0
Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO bOX 913, Dunedin 9054
Country [1] 295254 0
New Zealand
Primary sponsor type
Individual
Name
Yusuf Ozgur Cakmak
Address
Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO bOX 913, Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 294082 0
University
Name [1] 294082 0
Otago University
Address [1] 294082 0
Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO bOX 913, Dunedin 9054
Country [1] 294082 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296592 0
University of Otago, Human Ethics Committee(Health)
Ethics committee address [1] 296592 0
Room G22 Clocktower Building
University of Otago, Dunedin 9054
Ethics committee country [1] 296592 0
New Zealand
Date submitted for ethics approval [1] 296592 0
09/12/2016
Approval date [1] 296592 0
12/12/2016
Ethics approval number [1] 296592 0
H16/148

Summary
Brief summary
It has been shown that at the olfactory bulb, where smell is processed, neurons show pathological changes at (smell) olfaction-related neuronal system. Alzheimer disease(AD) and Parkinson's disease(PD) patients show a significant loss of olfactory performance. In sum, the functional regression of the smell function contributes to numerous neurological diseases and therefore, regaining the olfactory function is crucially important for a potential treatment for AD, PD, Dementia and appetite disorders.
Hypothesis: Vagal nerve fibers convey the visceral information to the olfactory bulb. Invasive Vagal Nerve Stimulation (VNS), using surgery, has been shown to decrease thresholds of the olfactory bulb neurons. This is directly associated with a lower detection threshold for the smell. It is also reported that invasive VNS increases the glucose uptake in the olfactory bulb. In a human study using invasive VNS, devices were implanted at vagal nerve sites in the neck region. Olfactory information processing was influenced and modulated with neck-implanted VNS devices. Results affirm the postulation that there is a strong correlation between VNS and olfactory bulb activity.
To date, Olfactory bulb activity modulation with VNS stimulation has only been achieved using invasive VNS techniques. If VNS stimulation could be achieved using a non-invasive technique, this has the potential to be a safe and effective treatment to improve olfactory bulb function for AD, PD Dementia and Appetite disorder patients. To date, there has been no study on the non-invasive VNS effects on olfactory function. In the present trial, we will investigate the efficacy of the non-invasive VNS (pain-free, electrical stimulation of the skin) on altering the olfactory function in healthy humans. Data collection and subsequent assessment will (i) achieve clarification of the efficacy of non-invasive direct and indirect VNS to modulate olfactory function, and (ii) distinguish the two distinct frequency effects on modulation of the olfactory threshold, olfactory discrimination and olfactory memory functions in humans.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 71414 0
Dr Yusuf Ozgur Cakmak
Address 71414 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 71414 0
New Zealand
Phone 71414 0
+64-03-479-4030
Fax 71414 0
Email 71414 0
yusuf.cakmak@otago.ac.nz
Contact person for public queries
Name 71415 0
Dr Yusuf Ozgur Cakmak
Address 71415 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 71415 0
New Zealand
Phone 71415 0
+64 3 479 4030
Fax 71415 0
Email 71415 0
yusuf.cakmak@otago.ac.nz
Contact person for scientific queries
Name 71416 0
Dr Yusuf Ozgur Cakmak
Address 71416 0
Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054
Country 71416 0
New Zealand
Phone 71416 0
+64 3 479 4030
Fax 71416 0
Email 71416 0
yusuf.cakmak@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
We published the results and the method/data/results/outcome is open access.
What supporting documents are/will be available?
No other documents available
Summary results
Have study results been published in a peer-reviewed journal?
Yes
Journal publication details
Publication date and citation/details [1] 1177 0
https://www.frontiersin.org/articles/10.3389/fnins.2018.00225/full
Publication date and citation/details [2] 1178 0
https://www.frontiersin.org/articles/10.3389/fnhum.2018.00533/full
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary
In non-invasive vagal nerve stimulation, ear skin is stimulated with low and high frequencies. Participant's olfactory functioning was monitored using near-infrared light imaging(NIRS), and assessed with two behavioural olfactory tests. Only high frequency, auricular stimulation was able to positively modulate the performance of the healthy participants in the (suprathreshold) olfactory tests, with significant differences in brain activity. In wrist stimulation study, twenty healthy, male, adults performed supra-threshold odor intensity tests for four food-related odorant samples before and after receiving high-, low-frequency stimulation and placebo (no stimulation), while brain activity was monitored by the NIRS. Only the high-frequency wrist skin stimulation showed effects for suppressing the intensity perception of the 3 odorant samples. These behavioral changes were coupled with significant changes in the brain activity.