New University of Michigan Tinnitus Discovery — Signal Timing

[PeterPan]

TFI is a poor indicator but I suppose it's a variable and they have used it in this graph to show the relationship.

Look at the green dots. These represent readings for people without the treatment.

There are many more green dots on the left of the vertical line than the right. This means that TFI is improving. But there are about the same number of green dots below and above the horizontal line, meaning that loudness is not changing.

I think that's encouraging because it is showing that the loudness measure is an objective measure (doesn't change during the control phase), and TFI is not (does change during the control phase, something we might expect from a self-assessment questionnaire).

 

[Karen1979]

Look at the green dots. These represent readings for people without the treatment.

There are many more green dots on the left of the vertical line than the right. This means that TFI is improving. But there are about the same number of green dots below and above the horizontal line, meaning that loudness is not changing.

I think that's encouraging because it is showing that the loudness measure is an objective measure (doesn't change during the control phase), and TFI is not (does change during the control phase, something we might expect from a self-assessment questionnaire).

Agreed.

The problem with a graph like this is there's just too much data! But they are used to show the relationship (good or bad, or nothing notable).

 

[Champ]

Short answer, it sure looks like better news than was expected.

Considering we're all used to studies that lack crucial elements like placebo and control groups, seeing that this study was so robustly done and produced such large volumes of data that all point to it being very effective is something none of us expected.

It was inevitable that effective treatments would come but nothing seems possible until it is.

 

[Nick47]

Well, given the p-value of 0.003 versus placebo, it's clearly effective for a significant number of people. OTO-313 and FX-322 use p-values of <0.5 as significant, so Dr. Shore's results are HIGHLY significant. That being said, it pretty much mirrors the smaller trial.

• 10% super responders with reductions ~40 dB = elimination of tinnitus
• 20% got big reductions in volume
• 20% got mild-moderate reductions in volume
• 10% mild reductions in volume
• 40% no change/worse readings.

Placebo got ~20% improvement of some sort (normal placebo values) and 80% no improvement/worse.

So a significant between-group difference gives a p-value of 0.003.

These are very rough figures looking at the density of the correlation.

Now before the paranoid thoughts start, worsening doesn't mean the treatment worsened them at all. It just means on the day of the test the tinnitus was worse.

Only 20-25% had worse TFI scores in the treatment group.

 

[Mathew Gould]

So after looking at the scatter chart, green means they never got the treatment? What percentage got better and what percentage got worse? If your tinnitus got worse from the treatment, did it go back to base level after the treatment was stopped?

 

[KoolKat]

Well, given the p-value of 0.003 versus placebo, it's clearly effective for a significant number of people. OTO-313 and FX-322 use p-values of <0.5 as significant, so Dr. Shore's results are HIGHLY significant. That being said, it pretty much mirrors the smaller trial.

• 10% super responders with reductions ~40 dB = elimination of tinnitus
• 20% got big reductions in volume
• 20% got mild-moderate reductions in volume
• 10% mild reductions in volume
• 40% no change/worse readings.

Placebo got ~20% improvement of some sort (normal placebo values) and 80% no improvement/worse.

So a significant between-group difference gives a p-value of 0.003.

These are very rough figures looking at the density of the correlation.

Now before the paranoid thoughts start, worsening doesn't mean the treatment worsened them at all. It just means on the day of the test the tinnitus was worse.

Only 20-25% had worse TFI scores in the treatment group.

OK, but with some extra tinkering of the device's settings on patients / cranking it to the max, those 40% who had no change will eventually get an improvement, right? I mean this makes no sense, why couldn't they get a reduction in tinnitus loudness too?

With all that you've seen, do you think we're headed in the right direction?

 

[Kam75]

So after looking at the scatter chart, green means they never got the treatment? What percentage got better and what percentage got worse? If your tinnitus got worse from the treatment, did it go back to base level after the treatment was stopped?

Many questions remain unanswered for the moment. We only have a small glimpse of the device's potential.

We will have to wait for the publication of the full Phase II results to know everything. I hope it will be soon.

It's a bit like waiting for the 25th of December for a kid

 

[Nick47]

With all that you've seen, do you think we're headed in the right direction?

@KoolKat, yes it works, just not for everyone versus the placebo, which works for even less by a highly significant amount.

I think it was Dr. De Ridder who said not everything works for everyone.

 

[Stanley Samwise]

I can sense a little bit of a negativity or worry creeping in here guys. Let's not forget - this device is the first of its kind to work, with a measured real reduction in loudness, compared to a control group. That's absolutely massive. And as someone said above, the standard deviation means most experienced somewhere around the 75% if I'm not mistaken. There is a treatment on the way, and it's going to open the floodgates I'm sure. In 5 years, who knows what the market for treatment is going to look like.

I can understand why a few ears prick up around the worsening, but at the moment, there's a lot of context missing. It's also unlikely that the device made people's tinnitus permanently worse; I do think there would've been some mention of that from Dr. Shore otherwise.

 

[Tomas80]

Well, given the p-value of 0.003 versus placebo, it's clearly effective for a significant number of people. OTO-313 and FX-322 use p-values of <0.5 as significant, so Dr. Shore's results are HIGHLY significant. That being said, it pretty much mirrors the smaller trial.

• 10% super responders with reductions ~40 dB = elimination of tinnitus
• 20% got big reductions in volume
• 20% got mild-moderate reductions in volume
• 10% mild reductions in volume
• 40% no change/worse readings.

Placebo got ~20% improvement of some sort (normal placebo values) and 80% no improvement/worse.

So a significant between-group difference gives a p-value of 0.003.

These are very rough figures looking at the density of the correlation.

Now before the paranoid thoughts start, worsening doesn't mean the treatment worsened them at all. It just means on the day of the test the tinnitus was worse.

Only 20-25% had worse TFI scores in the treatment group.

Statistics can be deceiving. 50% of participants had an improvement. It's like "with chicken". I'll eat one chicken, you none. Statistically, we both ate half the chicken.

Forgive my skepticism, but I really expected better results. At least 75% of the participants would deserve a moderate and higher reduction.

 

[AnthonyMcDonald]

I was digging around and found this:

"Here we demonstrate that unilateral sound exposure causes development of hyperactivity in both the contra and ipsilateral inferior colliculus in mice."

Effect of Unilateral Acoustic Trauma on Neuronal Firing Activity in the Inferior Colliculus of Mice​

This is interesting. The study shows IC hyperactivity remaining unchanged until a few weeks after heightened DCN hyperactivity following noise exposure. This proves that neurons have crossing fibers at every level of the auditory pathway and it takes time to spread throughout the brainstem. This also proves (and is confirmed by Thanos Tzounopoulous's research) that immediately solving the hyperactivity and dysfunction of the DCN (whether with Dr. Shore's device or a potassium channel opener) days/weeks after exposure could mitigate any hyperactivity in other parts of the auditory pathway and tinnitus development altogether. Furthermore, as I would assume, this could very well possibly prevent further spikes in chronic sufferers.

Could fixing DCN hyperactivity with Dr. Shore's device or XEN1101 in chronic sufferers possibly fix other hyperactivity along the higher levels of the auditory pathway? I guess that remains to be seen. I certainly hope so.

 

[Chinmoku]

So many purple points above the loudness change zero axis of the scatter-plot. I remember seeing something similar from the old, smaller trial and that always bothered me. I really hope those are loudness worsening cases that are unrelated to the device, but we also need to keep in mind the device is adjustable, the electrodes positioning can be changed and maybe the loudness reverts. The good thing is that the device seems to be interacting with the tinnitus brain network. If it interacts in the wrong direction, one can change the setting. I'm not sure the signal timing can be adjusted too. Is it fixed for everyone?

I'm in no condition to take a worsening or to hold on much longer, we need a bit of luck here, or maybe a ton of luck. For someone stable and mild or moderate, one-two years are not a walk in the park but doable, but for someone in agony and progressive they might as well be 20 years. I hope it comes out fast.

 

[AfroSnowman]

Well, given the p-value of 0.003 versus placebo, it's clearly effective for a significant number of people. OTO-313 and FX-322 use p-values of <0.5 as significant, so Dr. Shore's results are HIGHLY significant. That being said, it pretty much mirrors the smaller trial.

• 10% super responders with reductions ~40 dB = elimination of tinnitus
• 20% got big reductions in volume
• 20% got mild-moderate reductions in volume
• 10% mild reductions in volume
• 40% no change/worse readings.

Placebo got ~20% improvement of some sort (normal placebo values) and 80% no improvement/worse.

So a significant between-group difference gives a p-value of 0.003.

These are very rough figures looking at the density of the correlation.

Now before the paranoid thoughts start, worsening doesn't mean the treatment worsened them at all. It just means on the day of the test the tinnitus was worse.

Only 20-25% had worse TFI scores in the treatment group.

Did I miss something in the data about standard distributions? I see a super small p-value (0.003, right?). So 0.3% chance you'd get the results randomly. It is safe to assume that the effect is real. Awesome!

Where has there been any information released about the distribution of responders? I know we have the scatter plot, but my reading of it is that it doesn't show anything other than people at some point during the treatment reported different dB levels and that their reported TFI is correlated to the level of noise in their head.

Just wondering whether I missed something or if this is just conjecture.

 

[Monkee Man]

I'm dying for the device to finally come out so we can hear some real-world results and experiences, rather than numbers and graphs. The only aspect the data represents is the lowering of the tinnitus volume, which is revolutionary in itself if truly effective, but I wonder what effect could possibly come about for sound sensitivity and future spikes.

If Dr. Shore's device can somehow calm the hyperactivity in my brain to reduce my hyperacusis and susceptibility to tinnitus spikes and pain from noise in a way that allows me to resume normal life activities with some precautions (being out and about without earplugs in, hopefully being able to attend concerts/movies/other loud events with hearing protection, using headphones at a safe level, etc.), I wouldn't even care that much for lowering the baseline level of my tinnitus, to be honest. I am remaining cautiously optimistic until then... time will tell.

 

[Jerad]

View attachment 52246

Nice. That look suits you well; it's very becoming. lol

 

[Nick47]

Just wondering whether I missed something or if this is just conjecture.

@AfroSnowman, other than the p-value, the rest is conjecture from roughly looking at the distributions patterns.

 

[dj_newark]

I've asked Dr. Shore if the device should work for long standing tinnitus. This is our exchange:

Hi Dr. Shore,

Is there any reason to think that this treatment won't work for those who've had Tinnitus for a very long time? My Tinnitus started in 1990 and was severe by the mid-nineties.

I'm very curious if you think this can work for people like me and others I've spoken to who have had it for a very long time.

She responds by saying:

Many people in the trial had long lasting tinnitus.

I'm really glad to have that confirmed!

 

[Aussie Lea]

@AfroSnowman, other than the p-value, the rest is conjecture from roughly looking at the distributions patterns.

Where did you get the p-value for the Phase 2 trial results? That's what @AfroSnowman asked and you didn't answer lol.

 

[AfroSnowman]

Where did you get the p-value for the Phase 2 trial results? That's what @AfroSnowman asked and you didn't answer lol.

P-value is on the scatter plot slide, I was curious about where he was getting the distribution pattern.

 

[ColinUK]

Just get the device to market, then we will see if it works or not. Such a limited test group. I will not believe anything until we start getting lots of people on here saying it's worked for them.

 

[PeterPan]

Well, given the p-value of 0.003 versus placebo, it's clearly effective for a significant number of people.

This p-value is for the correlation between the change in TFI and the change in loudness during the active phase. I don't think this is indicative of the effectiveness of the device? Also, not sure why there would be a significant correlation during the active phase but no significant correlation during the control phase?

For example, if I am in the the control phase and have a good day, I would expect both the TFI and the loudness to be reduced and if I have a bad day, I would expect both the TFI and loudness to be elevated.

So many questions! I'm sure it will become a lot clearer once the publication comes out.

 

[Nobody19]

I can sense a little bit of a negativity or worry creeping in here guys. Let's not forget - this device is the first of its kind to work, with a measured real reduction in loudness, compared to a control group. That's absolutely massive. And as someone said above, the standard deviation means most experienced somewhere around the 75% if I'm not mistaken. There is a treatment on the way, and it's going to open the floodgates I'm sure. In 5 years, who knows what the market for treatment is going to look like.

I can understand why a few ears prick up around the worsening, but at the moment, there's a lot of context missing. It's also unlikely that the device made people's tinnitus permanently worse; I do think there would've been some mention of that from Dr. Shore otherwise.

Exactly! This is a start. Susan Shore is a scientist, she will run experiments on how to improve the device. Other researchers and pharma will also look at how it works and learn from there.

 

[Eric N]

Will people with better audiograms have better outcomes or doesn't it matter?

 

[Hottopic29]

I could modulate tinnitus before I even had tinnitus. I'm pretty sure people whose tinnitus changes by moving the neck does so just by adding a louder tone from a different source of body masking it...

 

[Fightthearmy]

Like you said previously, we are unlikely to see it in the NHS despite the clinically significant results. Someone will need to know how to test each patient's frequency, somatic location and set up the device. I would not attempt it myself so either way it will be a few thousand pounds through some private clinic. If it works then I will be more than happy to pay, but I would expect some sort of money-back guarantee or loan option offered, just in case it doesn't work. It looks like after 4-6 weeks you will know if you are a responder or not, so forking out £3,000 for a device you don't respond to and are stuck with is harsh.

Well, I'll be on sick leave indefinitely, until there's some coverage. It might be worthwhile to think whether covering for the expenses wouldn't be cheaper for society.

 

[Nick47]

It might be worthwhile to think whether covering for the expenses wouldn't be cheaper for society.

No, it's cheaper to pump us full of SSRIs and send us to the BTA, who will tell us to go for a walk or do a jigsaw puzzle.

I'm also going to add, as people are in meltdown over the scatter graph, that this was after 6 weeks.

It's interesting to see the graph after 12 weeks.

 

[Karen1979]

No, it's cheaper to pump us full of SSRIs and send us to the BTA, who will tell us to go for a walk or do a jigsaw puzzle.

I'm also going to add, as people are in meltdown over the scatter graph, that this was after 6 weeks.

It's interesting to see the graph after 12 weeks.

I was tentative in writing this as I don't want to give false hope. However, through "individual funding requests for specialised services" in the NHS, a clinician can request funding for a proven treatment. If a solid case is raised and the price of the device is, let's say cheaper than "medication", this could lead to a device being purchased, but, and I say but, it may be a postcode lottery. However, if one device is purchased, it could then used by a specialist clinician for several patients (after clinical use of 6 weeks of course). But the BTA would have to stand behind the device, and this would still take time but not as long as getting the device into mainstream. (I had a lengthy discussion with my clinical lead, he's supportive as he knows my suffering.)

 

[Nick47]

I was tentative in writing this as I don't want to give false hope. However, through "individual funding requests for specialised services" in the NHS, a clinician can request funding for a proven treatment. If a solid case is raised and the price of the device is, let's say cheaper than "medication", this could lead to a device being purchased, but, and I say but, it may be a postcode lottery. However, if one device is purchased, it could then used by a specialist clinician for several patients (after clinical use of 6 weeks of course). But the BTA would have to stand behind the device, and this would still take time but not as long as getting the device into mainstream. (I had a lengthy discussion with my clinical lead, he's supportive as he knows my suffering.)

Thanks for this. I would pay private if the indications were it could help.

The BTA are constantly under pressure to recommend Lenire as there is now a financial relationship between Neuromod and the BTA. Basically Neuromod sponsors some of the BTA events. If you read the BTA website, they are neutral towards it, yet some treatments that do have better evidence (Alprazolam/Clonazepam/tDCS/Deanxit/Gabapentin) are not recommended due to lack of robust evidence.

I think the BTA need to accept that there are no-size-fits-all treatments, treat us like adults, and say some of the above to help some people, and to speak to GP.

The fact the BTA were not tuned into the Palm Springs Hearing Seminar really shows poorly on them. POOR!

 

[Nick47]

This is an important point. What does your current audiogram look like? I have a circa -43 dB notch @ 4 kHz and would therefore have been excluded from using this device based on Dr. Shore's Phase 1 criteria. Thankfully, however, the team relaxed that particular criteria in Phase 2 and made it a max hearing loss of -50 dB.

Is this a 43 dB notch bilaterally or unilaterally? Is your tinnitus bilateral?

I'm sure one of the inclusion criteria in the clinical trials was unilateral tinnitus, yet a member of Tinnitus Talk who has bilateral tinnitus was part of the Phase 1 clinical trial. The inclusion criteria in Phase 2 clinical trial stated a minimum tinnitus duration of 6 months, preferably up to 1 year. However, Dr. Shore stated there were many long termers in the Phase 2. I dunno...

 

[UKBloke]

Is this a 43 dB notch bilaterally or unilaterally? Is your tinnitus bilateral?

I'm sure one of the inclusion criteria in the clinical trials was unilateral tinnitus, yet a member of Tinnitus Talk who has bilateral tinnitus was part of the Phase 1 clinical trial. The inclusion criteria in Phase 2 clinical trial stated a minimum tinnitus duration of 6 months, preferably up to 1 year. However, Dr. Shore stated there were many long termers in the Phase 2. I dunno...

This is my latest audiogram. Sorry for the appalling pic, I've got the world's worst steam-powered phone and the audiogram wasn't supplied on the greatest quality paper.

The "classic" noise-induced notched is evident in the right ear. The left ear rolls off at 4 kHz and doesn't recover much.

My tinnitus is bilateral, however, the left ear is most problematic and intrusive. I understand Dr. Shore's study eligibility criteria always preferred unilateral tinnitus but didn't demand it. Similar situation with the onset and duration criteria. On that basis I believe I can be a candidate for the treatment if everything pans out.