ANZCTR - Registration

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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 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]

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

Parkinson's Disease

Dementia

Appetite disorders

Condition category

Condition code

Neurological

Alzheimer's disease

Neurological

Parkinson's disease

Neurological

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]

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]

Change in Sniff-stick threshold test results (statistical difference in detection odours based on detection of the same odour after the electrostimulation).

Timepoint [1]

before and after 10 minutes of Transcutaneous Electrical Nerve Stimulation or 10 minutes of Placebo session

Secondary outcome [1]

% Change in Near Infrared Monitoring score of Frontal Cortex perfusion

Timepoint [1]

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

Sex

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

1/02/2017

Actual

7/02/2017

Date of last participant enrolment

Anticipated

1/03/2018

Actual

28/02/2018

Date of last data collection

Anticipated

2/03/2018

Actual

28/02/2018

Sample size

Target

Accrual to date

Final

Recruitment outside Australia

Country [1]

New Zealand

State/province [1]

OTAGO

Funding & Sponsors

Funding source category [1]

University

Name [1]

Otago University

Address [1]

Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO bOX 913, Dunedin 9054

Country [1]

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]

University

Name [1]

Otago University

Address [1]

Department of Anatomy
Otago School of Medical Sciences
University of Otago
PO bOX 913, Dunedin 9054

Country [1]

New Zealand

Ethics approval

Ethics application status

Approved

Ethics committee name [1]

University of Otago, Human Ethics Committee(Health)

Ethics committee address [1]

Room G22 Clocktower Building
University of Otago, Dunedin 9054

Ethics committee country [1]

New Zealand

Date submitted for ethics approval [1]

09/12/2016

Approval date [1]

12/12/2016

Ethics approval number [1]

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

Dr Yusuf Ozgur Cakmak

Address

Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054

Country

New Zealand

Phone

+64-03-479-4030

Fax

yusuf.cakmak@otago.ac.nz

Contact person for public queries

Name

Yusuf Ozgur Cakmak

Address

Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054

Country

New Zealand

Phone

+64 3 479 4030

Fax

yusuf.cakmak@otago.ac.nz

Contact person for scientific queries

Name

Yusuf Ozgur Cakmak

Address

Department of Anatomy
School of Biomedical Sciences
University of Otago
PO BOX 913, DUNEDIN 9054

Country

New Zealand

Phone

+64 3 479 4030

Fax

yusuf.cakmak@otago.ac.nz

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

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 Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

Source	Title	Year of Publication	DOI
Embase	Improvement of olfactory function with high frequency non-invasive auricular electrostimulation in healthy humans.	2018	https://dx.doi.org/10.3389/fnins.2018.00225
Dimensions AI	Non-invasive High Frequency Median Nerve Stimulation Effectively Suppresses Olfactory Intensity Perception in Healthy Males	2019	https://doi.org/10.3389/fnhum.2018.00533

N.B. These documents automatically identified may not have been verified by the study sponsor.

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Documents added manually

Documents added automatically