Tinnitus
Conditions
Keywords
Ear, Hearing
Brief summary
The purpose of this study is to determine whether a new device delivering a sound-based intervention (termed acoustic coordinated reset neuromodulation) has significant clinical benefit for people with intrusive tinnitus. It is hypothesised that the particular pattern of sound stimulation delivered by the device acts to break up patterns of synchronous nerve firing in the brain that may be responsible for the sensation of tinnitus. We will also measure brain activity in a subset of participants to determine if the intervention results in changes in brainwave activity.
Detailed description
Tinnitus affects a large number of people in the UK population but is a poorly understood disorder with no form of treatment that benefits everyone. One theory about tinnitus is that it is caused by altered patterns of synchronous nerve firing in the brains hearing centres. It is believed that conditions such as hearing loss lead to changes in how areas of the brain responsible for hearing are 'wired up' causing large areas of the brain to fire at the same time; this is believed to be a mechanism responsible for the sensation of tinnitus. Research suggests that this type of synchronous activity may be interrupted by presenting very specific sequences of sounds to the ears over several months. If sound stimulation can be used to break up patterns of synchronous activity in the hearing brain, then it is argued that it should also be effective in treating tinnitus. The German company ANM have patented a very specific algorithm of sound simulation that is delivered via headphones from a pocket-sized device. This treatment is currently being marketed by the private healthcare sector in Germany and very recently in the UK. The purpose of this study is to independently test the effects of this new therapy on tinnitus severity and related brain activity. We will gather information using questionnaires and listening tests, and make recording of electrical brain activity using electroencephalography (EEG).
Interventions
DEVICECR Neuromodulation
Ear level device which delivers patterned sound stimulation. The experimental arm will use the device fitted according to audiologist training given by the manufacturer/funder. An individually specified sound stimulation algorithm is hypothesised to interrupt tinnitus generating activity in the brain. For the first 12 weeks participants will be asked to wear the device every day for 6 hours, and in blocks of time not less than 1 hour. After 12 weeks participants will be unblinded and continue with the same experimental intervention. In weeks 13-36 participants will be asked to wear the device every day for 4 hours, in continuous blocks of at least 1 hour.
DEVICETinnitus masking
The active comparator uses the same ear level device and also delivers patterned sound but the stimulus will be determined according to an algorithm predicted not to break up tinnitus generating activity in the brain. It may have a masking effect. For the first 12 weeks participants will be asked to wear the device every day for 6 hours, and in blocks of time not less than 1 hour. After 12 weeks, the participants will be unblinded and the device algorithm will be reprogrammed in the same way as the experimental intervention. In weeks 13-24 participants will be asked to wear the device for 6 hours per day, in continuous blocks of at least 1 hour. In weeks 25-36 they will be asked to continue using the device every day for 4 hours, in continuous blocks of at least 1 hour.
Sponsors
University of Nottingham
University College, London
Nottingham University Hospitals NHS Trust
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Pure tone average \<60 dB HL in the ear where tinnitus is perceived * Must be able to hear all stimulation tones presented by the device * Chronic subjective tinnitus for more than 3 months * Dominant tinnitus frequency measured between 0.2 and 10 kHz * At least mild tinnitus score on the Tinnitus Handicap Inventory * Willing to wear the device for 4-6 hours daily during the trial * Sufficient command of English language to read, understand and complete the questionnaires * Able and willing to give informed consent
Exclusion criteria
* Objective tinnitus, Meniere's disease, craniomandibular induced Tinnitus * Pulsatile tinnitus * Intermittent tinnitus * Severe anxiety * Severe depression * Catastrophic tinnitus * Hearing-aids wearers for less than 9 months * Hearing-aid wearers with audiological adjustments within last 3 months * Absolute thresholds \> 70 dB on individual frequencies up to 8 kHz (unable to sufficiently hear the stimulus) * Taking part in another trial during the last 30 days before study start * The individually tailored training stimulus is uncomfortable or not acceptable to the participant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tinnitus Handicap Questionnaire (THQ) | Baseline (visit 2) and 12 weeks (visit 6) | Change in the global score on a 27 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Tinnitus Handicap Inventory (THI) | Baseline (visit 2) and 12 weeks (visit 6) | Change in the global score on a 25 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms. |
| Tinnitus Functional Index (TFI) | Baseline (visit 2) and 12 weeks (visit 6) | Change in the global score on a 25 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms. |
| World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) | Baseline (visit 2) and 12 weeks (visit 6) | The WHOQOL-BREF is a 26-item, multi-attribute questionnaire measure of health related quality of life. Outcome was measured as a change on Question 1: 'How would you rate your quality of life (over the past 4 weeks)?' There are 5 response options (Very poor=1; Poor=2; Neither poor nor good=3; Good=4; Very good=5). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction in self-perceived quality of life. |
| Percent Change From Baseline in Normalized Oscillatory Power in the Delta Brainwave Pattern as Measured by Electroencephalography (EEG) | Baseline (visit 2) and 12 weeks (visit 6) | Non-invasive recording to measure rhythmic patterns of spontaneous brain activity at rest. An a priori hypothesis targeted normalized delta rhythm. Band powers were calculated as percent change in delta brainwave pattern relative to change in total (1-90 Hz) EEG band. Comparison made between 'visit 2' and 'visit 6'. We used a Neuroscan system (SynAmps2 model 8050, Compumedics Neuroscan, Charlotte, NC, USA) and custom cap with 66 equidistant scalp electrodes (Easycap, GmbH, Germany). A central frontal electrode was used as ground and a nose-tip electrode as reference. Electrode impedances were maintained at 5 kΩ prior to recordings. Recording was done with an offline filter of 0.5 to 200 Hz pass-band and 1 kHz sampling rate. Recording was over a continuous 10-minute period. Participants were seated in a quiet, darkened soundproof booth and were instructed to relax, keep eyes open and fix gaze on a marker point. |
| Tinnitus Handicap Questionnaire (THQ) | Baseline (visit 2) and 36 weeks (visit 10) | Change in the global score on a 27 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 10' and so a positive change score indicates a reduction of tinnitus symptoms. |
Countries
United Kingdom
Participant flow
Recruitment details
First patient first visit, 28 May 2012 Last patient last visit, 26 February 2014
Pre-assignment details
217 screen fails: Ménière(6), neuroma(2), TMJ(3), hearing loss(2), new hearing-aid user(11), recent hearing-aid adjustments(2), severe anxiety(4), severe depression(5), pulsatile TI(7), somatic TI(17), intermittent TI(7), slight TI(35), catastrophic TI(6), pitch match not possible(7), pitch out of fitting range(56), prescription tones inaudible(47)
Participants by arm
| Arm | Count |
|---|---|
| CR Neuromodulation see Protocol section for details | 50 |
| Tinnitus Masking see Protocol section for details | 50 |
| Total | 100 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double-blind (0-12 Weeks) | Adverse Event | 2 | 0 |
| Double-blind (0-12 Weeks) | Dominant pitch match not possible | 0 | 1 |
| Double-blind (0-12 Weeks) | Lost to Follow-up | 1 | 0 |
| Double-blind (0-12 Weeks) | Pitch shifted out of fitting range | 1 | 1 |
| Double-blind (0-12 Weeks) | Withdrawal by Subject | 2 | 0 |
| Open Label Extension (12-36 Weeks) | Adverse Event | 2 | 3 |
| Open Label Extension (12-36 Weeks) | Lost to Follow-up | 6 | 8 |
| Open Label Extension (12-36 Weeks) | Pitch shifted out of fitting range | 1 | 1 |
| Open Label Extension (12-36 Weeks) | Prescription adjusted: tones inaudible | 1 | 0 |
| Open Label Extension (12-36 Weeks) | Withdrawal by Subject | 1 | 1 |
Baseline characteristics
| Characteristic | CR Neuromodulation | Tinnitus Masking | Total |
|---|---|---|---|
| Age, Continuous | 49.1 years STANDARD_DEVIATION 11.3 | 51.8 years STANDARD_DEVIATION 12.2 | 50.5 years STANDARD_DEVIATION 11.7 |
| Beck Anxiety Inventory | 4.7 units on a scale STANDARD_DEVIATION 4.7 | 5.4 units on a scale STANDARD_DEVIATION 6.6 | 5.1 units on a scale STANDARD_DEVIATION 5.7 |
| Beck Depression Inventory | 8.7 units on a scale STANDARD_DEVIATION 6.4 | 9.0 units on a scale STANDARD_DEVIATION 7.3 | 8.7 units on a scale STANDARD_DEVIATION 6.6 |
| Hearing level (better ear) | 13.1 decibel hearing level (dB HL) STANDARD_DEVIATION 10.2 | 14.3 decibel hearing level (dB HL) STANDARD_DEVIATION 12 | 13.7 decibel hearing level (dB HL) STANDARD_DEVIATION 11.2 |
| Hearing level (worse ear) | 18.5 decibel hearing level (dB HL) STANDARD_DEVIATION 12.4 | 18.7 decibel hearing level (dB HL) STANDARD_DEVIATION 12.4 | 18.6 decibel hearing level (dB HL) STANDARD_DEVIATION 12.3 |
| Sex: Female, Male Female | 17 Participants | 37 Participants | 54 Participants |
| Sex: Female, Male Male | 33 Participants | 13 Participants | 46 Participants |
| Tinnitus Handicap Inventory | 40.0 units on a scale STANDARD_DEVIATION 17.4 | 40.9 units on a scale STANDARD_DEVIATION 15.8 | 40.2 units on a scale STANDARD_DEVIATION 16.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 50 | 3 / 50 |
| serious Total, serious adverse events | 0 / 50 | 0 / 50 |
Outcome results
Primary
Tinnitus Handicap Questionnaire (THQ)
Change in the global score on a 27 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms.
Time frame: Baseline (visit 2) and 12 weeks (visit 6)
Population: We have analyzed both complete case and multiple imputed data for the mean change in global THQ score from baseline (visit 2) to 12 weeks (visit 6). Here we report complete case data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | Tinnitus Handicap Questionnaire (THQ) | 3.75 units on a scale | Standard Deviation 13.29 |
| Tinnitus Masking | Tinnitus Handicap Questionnaire (THQ) | 4.02 units on a scale | Standard Deviation 9.56 |
Secondary
Percent Change From Baseline in Normalized Oscillatory Power in the Delta Brainwave Pattern as Measured by Electroencephalography (EEG)
Non-invasive recording to measure rhythmic patterns of spontaneous brain activity at rest. An a priori hypothesis targeted normalized delta rhythm. Band powers were calculated as percent change in delta brainwave pattern relative to change in total (1-90 Hz) EEG band. Comparison made between 'visit 2' and 'visit 6'. We used a Neuroscan system (SynAmps2 model 8050, Compumedics Neuroscan, Charlotte, NC, USA) and custom cap with 66 equidistant scalp electrodes (Easycap, GmbH, Germany). A central frontal electrode was used as ground and a nose-tip electrode as reference. Electrode impedances were maintained at 5 kΩ prior to recordings. Recording was done with an offline filter of 0.5 to 200 Hz pass-band and 1 kHz sampling rate. Recording was over a continuous 10-minute period. Participants were seated in a quiet, darkened soundproof booth and were instructed to relax, keep eyes open and fix gaze on a marker point.
Time frame: Baseline (visit 2) and 12 weeks (visit 6)
Population: The EEG assessment was offered only to the first 50 participants enrolled at the Nottingham site. We have analyzed only complete case data for the mean change in delta band power from baseline (visit 2) to 12 weeks (visit 6).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | Percent Change From Baseline in Normalized Oscillatory Power in the Delta Brainwave Pattern as Measured by Electroencephalography (EEG) | 0.001 Percent change | Standard Deviation 0.01 |
| Tinnitus Masking | Percent Change From Baseline in Normalized Oscillatory Power in the Delta Brainwave Pattern as Measured by Electroencephalography (EEG) | 0.004 Percent change | Standard Deviation 0.013 |
Secondary
Tinnitus Functional Index (TFI)
Change in the global score on a 25 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms.
Time frame: Baseline (visit 2) and 12 weeks (visit 6)
Population: We have analyzed both complete case and multiple imputed data for the mean change in global TFI score from baseline (visit 2) to 12 weeks (visit 6). Here we report complete case data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | Tinnitus Functional Index (TFI) | 2.38 units on a scale | Standard Deviation 19.7 |
| Tinnitus Masking | Tinnitus Functional Index (TFI) | 4.45 units on a scale | Standard Deviation 14.85 |
Secondary
Tinnitus Handicap Inventory (THI)
Change in the global score on a 25 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction of tinnitus symptoms.
Time frame: Baseline (visit 2) and 12 weeks (visit 6)
Population: We have analyzed both complete case and multiple imputed data for the mean change in global THI score from baseline (visit 2) to 12 weeks (visit 6). Here we report complete case data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | Tinnitus Handicap Inventory (THI) | 2.84 units on a scale | Standard Deviation 14.89 |
| Tinnitus Masking | Tinnitus Handicap Inventory (THI) | 1.64 units on a scale | Standard Deviation 10.81 |
Secondary
Tinnitus Handicap Questionnaire (THQ)
Change in the global score on a 27 item, multi-attribute questionnaire measure of the functional impact of tinnitus (0-100 scale). Change was computed as 'visit 2' - 'visit 10' and so a positive change score indicates a reduction of tinnitus symptoms.
Time frame: Baseline (visit 2) and 36 weeks (visit 10)
Population: We have analyzed both complete case and multiple imputed data for the mean change in global THQ score from baseline (visit 2) to 36 weeks (visit 10). Here we report complete case data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | Tinnitus Handicap Questionnaire (THQ) | 5.41 units on a scale | Standard Deviation 15.64 |
| Tinnitus Masking | Tinnitus Handicap Questionnaire (THQ) | 6.01 units on a scale | Standard Deviation 10.52 |
Secondary
World Health Organization Quality of Life Questionnaire (WHOQOL-BREF)
The WHOQOL-BREF is a 26-item, multi-attribute questionnaire measure of health related quality of life. Outcome was measured as a change on Question 1: 'How would you rate your quality of life (over the past 4 weeks)?' There are 5 response options (Very poor=1; Poor=2; Neither poor nor good=3; Good=4; Very good=5). Change was computed as 'visit 2' - 'visit 6' and so a positive change score indicates a reduction in self-perceived quality of life.
Time frame: Baseline (visit 2) and 12 weeks (visit 6)
Population: We have analyzed both complete case and multiple imputed data for the mean change in Q1 score from baseline (visit 2) to 12 weeks (visit 6). Here we report complete case data.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| CR Neuromodulation | World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) | -0.21 units on a scale | Standard Deviation 0.64 |
| Tinnitus Masking | World Health Organization Quality of Life Questionnaire (WHOQOL-BREF) | -0.11 units on a scale | Standard Deviation 0.61 |