New University of Michigan Tinnitus Discovery — Signal Timing

[Utdmad89]

A very good analysis! My original count was not quite right but I did notice that a large proportion did not complete all aspects of the study.

Looking again, of the 99 finally enrolled, 43 did not follow the protocols in some way. They were marked in the ITT group. The actual study size was 56, although the ITT were included separately. Whilst the results are promising, it definitely reduces the quality of the study as we have a smaller sample size.

Yes, I had to look a few times at this to wonder what the heck was going on here. It shows that the group that had placebo first did not benefit from the treatment after the washout. A really bizarre finding and I'm surprised no one else has brought this up as contentious?

Overall it's in the general direction of something positive, however I do think we need to run a more critical eye over things, rather than running off to get a Susan Shore tattoo.

This certainly isn't a Frequency Therapeutics type scenario as it's clearly showing responders, but we should keep things in check and not only see what we want to see.

So does this mean it's one big placebo?

 

[Nick47]

So does this mean it's one big placebo?

No. It looks like it works (for some) but the 2nd treatment group just cannot be ignored or explained at this stage. I'm now leaning towards what @Markku said a few pages back in that he expects the real effect to be between Lenire and the preliminary results. I hold Dr. Shore in high regards but with the number failing to complete all protocols and the 2nd treatment arms, it has cast some doubt on the efficacy. @PeterPan was right to bring the points to our attention as they need questioning. I'm suffering badly at times and want this to be effective for as many as possible, but I cannot unsee what's there and cherry pick the parts I want to see. Maybe we will get some feedback from the TRI 2023 conference on what the researchers thought of the paper.

For all Dr. Shore's scientific integrity, she will feel pressure from us, stakeholders and the funding agencies to get it to market.

In short, it seems to work in some. However, my doubts are:

1) How many get clinical benefit?
2) How much benefit?

I would like feedback from other members.

 

[DimLeb]

I appreciate the effort here but this is the equivalent of tearing your ACL, going to physical therapy once, and saying that you feel a little bit better but your knee is still pretty wrecked.

We just don't know what happens if you use the device for 12 months rather than 1 month, or for 3 hours a day instead of 30 minutes. There's too much of a possibility that the reductions will compound with further treatment to draw any conclusions about the total reduction possible based on one round of treatment.

Yeah, of course, all is, frustratingly, still speculation. I really hope we can abuse (in a good way) the device to bring the numbers down even more. ANY objective reduction is a huge step. Maybe some people will have total tinnitus elimination, maybe some will not respond at all. But at this point, we can only work with what we've got.

 

[Markku]

Maybe we will get some feedback from the TRI 2023 conference on what the researchers thought of the paper.

This is a good idea. I'm sure @Hazel will put out some feelers. I bet not many are aware of this latest study being published yet since the conference is this coming week and the study was published just on Friday.

But in general it's also nice to get some thoughts from the folks there (like how many have paid close attention to Dr. Shore's work in general over the past years, etc.)

Neuromod folks will also be at the conference. I wish Dr. Shore had attended this one too.

 

[AnthonyMcDonald]

There could be some type of of unknown plasticity that's going on with the second group, post washout. Maybe the auditory stimulation exclusively fucked something up in the DCN, maybe waiting longer would have done the trick, we don't know. I think that's potentially why Dr. Shore excluded them. But that's all speculation, we can only wait and see. There could be so many factors at play here.

 

[Jonno02]

I don't think it's one big placebo, but I feel there may be a bit of selectivity in their data reporting.

There's probably a psychological aspect to being in a study like this. It appears to me that both groups responded fairly similarly to the control treatment and showed a slight reduction.

Is there an element, from group 2, that they were then convinced they had been given the active treatment first since the placebo resulted in a slight volume decrease? 'The volume went down with the first treatment, therefore I know this next one is the control,' when the opposite was true? I have been guilty of 'OMG I think my tinnitus is going down' because I've started some super potent bio-active form of magnesium. When in reality it was doing absolutely nothing.

Were there some super responders within group 1 that make it look insanely good? Or inversely, were there some zero-sum responders in group 2 that make it look worse? Were there any statistical outliers in either data set? Was the dB reduction data statistically (not) normal? Group 2 have a marginally smaller population, making each individual case (especially outliers) contribute more to the graph in question.

Unfortunately there's a million questions and unless we get the raw data or issues like these are addressed at a later date, we just won't know.

What I don't like is that the graph in question is for ITT, so includes dropouts, those that didn't adhere to the guidelines for use etc. Why don't we have a graph for PP (those that strictly adhered to the instructions for use) results for dB reduction too?

Some people prefer ITT, but did group 1 have such a good response because they got together and decided to use the device for 3 hours a day (ITT) whereas group 2 stuck to the protocol (PP). Or did a few people from group 2 decide it wasn't for them and not use the device properly but as it's ITT, their data is included anyway?

 

[F-u-T]

In short, it seems to work in some. However, my doubts are:

1) How many get clinical benefit?
2) How much benefit?

I think you are spot on. I also can't overlook the worsenings reported in the study.

 

[Jim Vasilakis]

Lenire doesn't work. Period. If Dr. Shore's device is slightly better than Lenire, then it means it won't help the majority of people significantly.

I'm sorry but I really don't get how we have gone from a 75% loudness reduction to just "slightly better than Lenire".

 

[Jonno02]

Lenire doesn't work. Period. If Dr. Shore's device is slightly better than Lenire, then it means it won't help the majority of people significantly.

I'm sorry but I really don't get how we have gone from a 75% loudness reduction to just "slightly better than Lenire".

We haven't. The study could say '90% of people cured' but we don't REALLY know until people get their hands on it, all we can do at this moment in time is take their results at face value.

 

[UKBloke]

My initial thoughts regarding the Group 1 placebo anomaly. I might be grasping at straws but the trial exclusion criteria states that no other tinnitus treatment should have been undertaken 6 months prior to the trial, however, the initial washout period was only 6 weeks. Why might this be significant?

We know that the placebo group received the audio component only. Audio alone is evidently not considered a valid treatment for tinnitus as far as the UMich team is concerned (which is why they used it for placebo), however, standalone audio protocols have been considered a kind of tinnitus treatment before; masking for example, notched audio etc.

If I had attempted to enter the trial having just undergone 6 weeks of standalone audio treatment, would they have prohibited me from participating based upon their, no tinnitus treatment for 6 months prior, exclusion criteria? By running the initial placebo group on audio alone but only washing out for 6 weeks have they violated their own exclusion criteria going into Group 2? Should the washout period have been 6 months instead?

 

[Nick47]

I'm sorry but I really don't get how we have gone from a 75% loudness reduction to just "slightly better than Lenire".

Out of desperation and hope + the preliminary results in December 2022. I think it was @Mentos who said we need to wait for the publication, "the devil is in the details."

How many headlines in the newspaper make bold scientific claims, knowing less than 1% will click the link to the study?

 

[KoolKat]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

 

[AnthonyMcDonald]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

The main reason why it isn't making headlines is the scam empire of TRT and other charlatans advertising their overpriced nonsense and quackery, also maskers/hearings aids/American Scam Association is doing their best to muffle the results as much as possible, imo.

 

[Jupiterman]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive.

I wouldn't be surprised.

A not too dissimilar thing happened with one of the main researchers at Frequency Therapeutics.

It's not uncommon for people to step down when they KNOW their ship is about to crash. Look what happened with Nicola Sturgeon, the Scottish First Minister back in February. Her resignation shocked everyone! That is until the police were searching her house not long afterwards, suspicious of financial irregularity in her political party.

The truth of this contraption will come out in due course.

I think, as others have stated on this thread, it'll likely be an improvement on Lenire but not as much as is being hoped for. I also think it'll work (if indeed it does work at all) better on those with milder tinnitus; the ones who will habituate within 18 months regardless.

My money is still on a pill being the first effective treatment for tinnitus.

 

[Utdmad89]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

It's really depressing. That was the last shot for probably a long time.

 

[Markku]

@Nick47, @Markku, if you guys were betting men, are you all in or no?

Ask me once we have interviewed Dr. Shore. I tread carefully after how Lenire turned out to be. But the situation here is different (substantially more rigorous research, studies, control groups, results, etc.), so I do look forward to the real world results.

@Hazel is on standby to fly to Michigan to interview her, and one of our members will be joining her (he's a professional videographer who wanted to volunteer his services).

It was our hope that we could have done the interview with NDA in place before the publication came out and then publish the interview right after, but that didn't pan out (not our fault).

We hope to deliver the goods as soon as possible though. We will keep a close eye on this thread in preparation of it, so all these questions and concerns you have will not go to waste.

And speaking of real world results, even the interview won't be the be-all and end-all, it's the real world experiences we start to collect the moment the device is out. Here's to that!

 

[Tomas80]

Whether this device, which we are waiting for so impatiently, really works, we will find out only when we use it for 6 weeks. Everything else is conjecture. Hopefully I'll have it on my head as soon as possible...

 

[ErikaS]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

I think Dr. Shore retired from her full time position because 1) She is in her 70s. She has dedicated many years to the position, research and field. Totally understandable as to why she is retiring from the University in my opinion, this is a natural progression of life, 2) She wants to be ready for a quick and efficient mass distribution of an intervention that she put 20 years of work into. It's not like she's quitting or shutting down Auricle Inc. It's actually the opposite based on what she shared with us through @Markku's post regarding her retirement.

It's not perfect. Nothing is. But we have nothing else and I still believe this will be a far better intervention than Lenire. Let's not forget @linearb's great response to it in the Phase 1 trial. And he didn't/doesn't have mild tinnitus. I honestly wish they would just start with distribution now/allow direct consumer purchase through an audiologist, but we will just have to wait and hope for a positive outcome.

 

[Fightthearmy]

Who were the most likely dropouts of each group? Does getting the active treatment first push you to drop out for different reasons than if you had gotten the sham from the outset? For instance, were those who got the sham first (Group 2) more likely than the other group to drop out because of low benefit? In any case, whether you finished the study or dropped out, your data weighed in equally as everyone's else in the ITT analysis, I suppose, with the missing data being imputed. (So in my mind, it would make sense and not so bizarre as Nick47 would have it that Group 1 showed better efficacy and it justifies why the paper focuses its attention mostly on the first group.)

Missing data
Sensitivity analyses will be performed to evaluate the robustness of the primary effectiveness results. Several different methodologies to impute missing data will be used to evaluate the robustness of the results: 1. A worst-case approach will be used to impute values for missing visits. If a participant is missing data at the visit for the endpoint, the baseline value will be imputed for the missing value.

If I had attempted to enter the trial having just undergone 6 weeks of standalone audio treatment, would they have prohibited me from participating based upon their, no tinnitus treatment for 6 months prior, exclusion criteria? By running the initial placebo group on audio alone but only washing out for 6 weeks have they violated their own exclusion criteria going into Group 2? Should the washout period have been 6 months instead?

It would have had to be 6 months for both Group 1 and Group 2. I'm trying to figure out if this would not have entailed some disadvantage in observing Group 1...?

Also, when they say worsening of tinnitus, what does this mean? It's not like they likely did any follow-up of the subjects who dropped out because of a reported a worsening? (A handful of times when I've used some masking or the ACRN gimmick, I've perceived as a temporary worsening of tinnitus, but permanent? No.)

 

[Gb3]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

No, if anything, Dr. Shore thought the results were sooooo promising that she retired and will double dip on her income from Auricle and her pension. Your reasoning doesn't make sense and only a paranoid person would think that.

Do we know if they have submitted an application to the FDA?

 

[Josh59]

It would be interesting to know the reasons why patients have worsened.

Could their somatosensory tinnitus be reactive to sound? If so, this would prove that it is possible to have somatic tinnitus that is reactive to sound, and this could be in the context of hyperacusis + somatosensory tinnitus.

This is a question that I asked @Hazel for her forthcoming trip to Dublin (Tinnitus Research Initiative Conference 2023).

Did they have mild underlying hyperacusis?

Was the aggravation just temporary?

Finally, was the aggravation due solely to the sound or due to the nerve stimulation?

If it's nerve stimulation, it would be interesting to know more. It might confirm that over-stimulation of the trigeminal and dorsal nerves when you have somatosensory tinnitus could, over time, make it worse.

That's how I feel, my somatic tinnitus gets worse beyond the sound.

 

[UKBloke]

Also, when they say worsening of tinnitus, what does this mean?

Quite. This is the question I want to know the answer to the most.

 

[Jonno02]

Aside from the ITT comments above stating that missing patient data was input as baseline, which is good practice as it gives a worst case scenario and is encouraging, I know that when I'm hyper focussed on my tinnitus, like back when I was trying every supplement under the sun, I would have good days and bad days. Periods of time I was convinced it was reducing in volume (it wasn't) and days where it seemed louder than baseline.

It's a very difficult condition to characterise, even with dB calibrated software, as tinnitus is so dynamic and there seems no rhyme or reason as to why we have good or bad days and the additional emotional response this provokes.

Even tone matching was incredibly hard for me as my tinnitus disappears with any tone Hz and so I'd need to wait until it came back to try another tone/volume. I'm still not 100% where my 9-14 kHz tones fall.

For some people, myself included, when we hyper focus on the tinnitus, even on a quiet day, it can seem unbearable. I assume there's quite a few people in the study that also fall into this category and so a reduction in volume might be overlooked; as they're stressed enough about it to seek out a clinical study.

I think a myriad of factors have contributed to Group 2 looking less than stellar; which have been discussed in good detail in the last few pages. But that doesn't negate Group 1 looking great.

We have no repeats to draw conclusions from, we only have 1 of each group. In my job I'm required to prove things 3 times (1 is an anomaly, 2 is luck, 3 is a trend) but that's just not possible for this clinical trial as you'd need 6 groups!

I don't think this device is anywhere near the state of Lenire though. We can't just forget all of the previous results and the years of research that have gone into this. It's unfair to start drawing conclusions about Dr. Shore, her team or device based on one dataset when we aren't privy to the raw data nor all of the information.

 

[Lurius]

Would love to see a price tag on this thing, so I can make plans.

 

[ErikaS]

It would be interesting to know the reasons why patients have worsened.

Could their somatosensory tinnitus be reactive to sound? If so, this would prove that it is possible to have somatic tinnitus that is reactive to sound, and this could be in the context of hyperacusis + somatosensory tinnitus.

This is a question that I asked @Hazel for her forthcoming trip to Dublin (Tinnitus Research Initiative Conference 2023).

Did they have mild underlying hyperacusis?

Was the aggravation just temporary?

Finally, was the aggravation due solely to the sound or due to the nerve stimulation?

If it's nerve stimulation, it would be interesting to know more. It might confirm that over-stimulation of the trigeminal and dorsal nerves when you have somatosensory tinnitus could, over time, make it worse.

That's how I feel, my somatic tinnitus gets worse beyond the sound.

I can confirm that my somatic sound is very reactive to sound. This sound is where I had my sudden hearing loss, very high-pitched electric frequency crap ranging from 12 kHz - 15 kHz. This was the first sound that came on, and I can modulate it with jaw movements.

What is interesting is all my other sounds that came on in the 1-3 months following the first sound onset that are mid to lower range sounds where I don't show hearing loss, none of those seem to be somatic. So just the sound where I had the SSHL.

I am sure I'm not the only one in this community that experiences a reactive somatic tinnitus sound so I agree, a very good question to ask.

Would love to see a price tag on this thing, so I can make plans.

I remember reading in their general plan for production and distribution of the device that consumer financing would be available. I would expect this from Dr. Shore as she is well aware of the financial burden this condition can leave many in, let alone just life in general these days.

 

[Lurius]

I remember reading in their general plan for production and distribution of the device that consumer financing would be available. I would expect this from Dr. Shore as she is well aware of the financial burden this condition can leave many in, let alone just life in general these days.

I'm mostly curious because the currency in my country is currently doing a softcore collapse and if this keeps continuing, all the money I've saved up for this is not going to amount to much. So I'll either have to wait until times improve or it becomes available in my country.

 

[EDDTEKK]

I am very curious how fast Auricle can commercialize this treatment. They should hurry because Lenire will disappoint a lot of people and they might not invest some thousands of dollars again to another "bimodal treatment".

 

[Hardwell]

I'm mostly curious because the currency in my country is currently doing a softcore collapse and if this keeps continuing, all the money I've saved up for this is not going to amount to much. So I'll either have to wait until times improve or it becomes available in my country.

Save yourself some trouble and don't worry about the unknown. You could be potentially causing yourself anxiety and stress around your affordability of a device that doesn't work well enough to merit buying. I'm not saying that's the case, but it doesn't seem logical to worry about your financing of it yet.

 

[BadNeighbors]

I'm starting to wonder if this is the real reason Dr. Shore retired abruptly and is so secretive. Come on Dr. Shore, you can do it

I also wonder why these results didn't make major headlines or is breaking news.

@Nick47, @Markku, if you guys were betting men, are you all in or no?

The University of Michigan had a press release about it. Last time I quit a job, no one wrote a press release.

And, she is still affiliated with the University of Michigan. While obtaining emeritus status doesn't mean she left on good terms, not obtaining this status would certainly mean she left on bad terms and was being pushed out. It seems to me that she left on a high-note. Retiring right as a big publication comes out is very much retiring on your own terms.

Finally, I don't think the results are major headlines because most people wouldn't care about this. It is terribly meaningful for us, but the vast majority of the population wouldn't care in the slightest. The top headline for the NYTimes today was the war in Ukraine; WSJ's top headline is the SEC suing Binance; Bloomberg's is Apple's new headset; Fox's is a human interest story about mom/kid dying in plane crash; WaPo's is the war in Ukraine; USA Today's war in Ukraine; Business Insider's is Apple headset; and so on. While Dr. Shore's device is important to me, Apple is much more important to investors/consumers and the war in Ukraine is much more important as well.

I don't think the retirement is a bad thing. It is jarring that the Shore Lab is shutting down, but the fact that she is transitioning to a role in the private world and retained a connection to the university is reassuring.

 

[Stayinghopeful]

Finally, I don't think the results are major headlines because most people wouldn't care about this. It is terribly meaningful for us, but the vast majority of the population wouldn't care in the slightest.

This. Plus, even the majority of people with tinnitus probably don't care. I know when my tinnitus was very mild, I wouldn't have cared. Unless Auricle wanted to pour millions into marketing like Lenire, it will fly under the radar for longer than it should IF it proves to give meaningful relief to the majority of sufferers.