New University of Michigan Tinnitus Discovery — Signal Timing

[Ryan Scott]

Code written by scientists is always a mess, that's just how it is. It doesn't necessarily correlate with the quality of the research. A Ph. D. doesn't automatically give 10 years of software development experience.

As a chemical engineer, I can confirm our coding is very messy lol. You can't really go to school for 6+ years for your profession, then go back for a degree in an entire new field of study.

I am kind of confused, can you sum it up for me why people are complaining about the coding language to begin with? Did they not get a software engineer involved in the development?

 

[UKBloke]

The device worked so well that the crossover was invalidated because the improvements continued through the washout phase.

I'm not so sure I agree with this. I believe the crossover was invalidated due to the contradiction in what they considered a treatment-free period to be. Entry into the trial required patients to have not undergone any tinnitus treatment for <12 weeks. Curiously, however, the washout phase was only 6 weeks. On paper at least those subjects coming out of the crossover and going into Phase II would still be prone to the effects of Phase I.

I put this specific point to Dr. Shore through the Tinnitus Talk Q&A but despite her graciously answering many questions from other members, she didn't answer or clarify my question. Unless they mixed the timings for a specific reason (I can't fathom why by the way), then this aspect of the trial design seems to me very strange. I'm not saying it invalidated the trial but I do think it seriously weakened it.

 

[Tryn2BHopeful]

I agree! And I also have to say, isn't it exciting that we can even say there is SOMETHING that we are waiting on? Back in 2016 when my tinnitus started, there was nothing I was remotely excited about and now we are talking about m o n t h s! Yes, I'm trying not to put all my eggs in one basket but still, there is something percolating!

Agreed. While I don't know if I have a chance of the device helping me at all, now being 8 months into this mess, if a new treatment manages to come out that could help me, it would be amazing luck. Maybe it is false hope, but it is hope.

 

[IYIiKe]

As someone new to tinnitus, I am genuinely excited about the hope that Dr. Shore's device has given folks. Regardless of its efficacy, those who believe their tinnitus resides at DCN -- this is the sort of that Hail Mary that I am not counting on but happy to hope/watch for. I feel it's probably equally likely (and by that I mean unlikely), that my tinnitus resolves itself on its own.

I think this healthy skepticism/tempered optimism is good for those here -- who have likely read on the numerous other types of treatment(s) that have come and gone. However, the doom/gloom at the other end of the spectrum has to be avoided as well.

I would suggest that folks temper the disdain of well-meaning studies. Any time Dr. Shore gets an article, it sends out an outpost reminding commercial entities that there is both potentially new science and financial opportunities out there, even if current treatments fall flat on expectations. Even if each study ultimately falls flat for the next few decades, it's possible a cumulative effect of small, minuscule advancements leads to a better life for someone in the future -- if not us.

Having worked with folks in and as a spouse of someone who recently escaped Academia, I can't help but suggest the expectations for a perfect study, perfect product, et al -- are VERY lofty expectations. Typically a grant will only cover so many bodies in the lab, and the amount of time for all involved and effort dedicated to all aspects are immense for the pay. At the end you're beholden to publishers who make inane requests and ask you to re-format your entire study for their single publication.

Work life balance is trash in academia, especially for the grunts/doctoral candidates generating a lot of the research.

All this to say you can indeed have brilliant minds and ideas presented with imperfect -- and even amateur in some aspects -- results. I am still hopeful that a product will be delivered within the next two years and, like many of you, I would be jumping at the bit to give it a shot.

Until next time my fellow EEEEEEEEEEEEE brethren/sisters.

 

[dj_newark]

I'm not so sure I agree with this. I believe the crossover was invalidated due to the contradiction in what they considered a treatment-free period to be. Entry into the trial required patients to have not undergone any tinnitus treatment for <12 weeks. Curiously, however, the washout phase was only 6 weeks. On paper at least those subjects coming out of the crossover and going into Phase II would still be prone to the effects of Phase I.

I put this specific point to Dr. Shore through the Tinnitus Talk Q&A but despite her graciously answering many questions from other members, she didn't answer or clarify my question. Unless they mixed the timings for a specific reason (I can't fathom why by the way), then this aspect of the trial design seems to me very strange. I'm not saying it invalidated the trial but I do think it seriously weakened it.

No, the crossover was invalidated, basically, because the device worked too well. And the effects of the treatment lasted through the washout phase and into Phase 2 where the first group was meant to have the placebo.

The subjects going into Phase 2 would be prone to the effects of Phase 1 only if the device worked better than expected. 6 weeks of not using the device is actually a long time.

This did not happen in the first clinical trial where the treatment phases and washout were 4 weeks. The subjects using the device returned to baseline and the crossover worked as designed in that trial. This suggests to me that using the device longer makes the device more effective.

This is exactly what Dr. Shore said:

A crossover study is the strongest possible design for a clinical trial, but only if there is recovery (or return to baseline) after the first treatment period during the washout phase. This worked well for the first pilot study with 4 weeks of treatment (Marks et al, 2018). For that study, the majority of subjects' tinnitus had mostly returned to baseline after the 4 week washout. For the second study we used 6 weeks of treatment and 6 weeks of washout before the crossover as we expected that we would see a return to baseline after 6 weeks of washout. We did not expect that the treatment would work so well after 6 weeks that there was no return to baseline during the washout. What we saw was that the treatment after 6 weeks was so long lasting that we did not see recovery. In fact, we saw a continued treatment effect up to 12 weeks (and beyond). For that reason the crossover did not work for the second study. This is called a "crossover effect" and it means that the second treatment period was biased by the first period. When that happens, it is not statistically valid to analyze the second half of the study. That is why we focused our analysis only on the first period.

 

[UKBloke]

No, the crossover was invalidated, basically, because the device worked too well. And the effects of the treatment lasted through the washout phase and into Phase 2 where the first group was meant to have the placebo.

The subjects going into Phase 2 would be prone to the effects of Phase 1 only if the device worked better than expected. 6 weeks of not using the device is actually a long time.

This did not happen in the first clinical trial where the treatment phases and washout were 4 weeks. The subjects using the device returned to baseline and the crossover worked as designed in that trial. This suggests to me that using the device longer makes the device more effective.

This is exactly what Dr. Shore said:

Again this doesn't answer the, no tinnitus treatment for <12 weeks entry criteria question.

I can't put words into their mouths but it seems to me they hedged their bets and used the 12 week entry criteria to ensure candidates were absolutely treatment free at the start of the trial. They did not apply that criteria to the washout and no amount of quoting Marks et al will change that.

I've always said I believe Dr. Shore has done good science. But this clinical trial is the basis upon which they'll market the device. Until they address the 12/6 week question (which I accept may have a perfectly innocent explanation), I won't consider the trial to have been properly conducted.

 

[Jonno02]

Again this doesn't answer the, no tinnitus treatment for <12 weeks entry criteria question.

I can't put words into their mouths but it seems to me they hedged their bets and used the 12 week entry criteria to ensure candidates were absolutely treatment free at the start of the trial. They did not apply that criteria to the washout and no amount of quoting Marks et al will change that.

I've always said I believe Dr. Shore has done good science. But this clinical trial is the basis upon which they'll market the device. Until they address the 12/6 week question (which I accept may have a perfectly innocent explanation), I won't consider the trial to have been properly conducted.

It kinda does though.

They chose 12 weeks for any other type of treatment as they would have no way of knowing the return to baseline time for treatments other than their own. 3 months seems like a reasonable time for tinnitus to return to normal levels for a patient based on their own first study's return to baseline of 4 weeks.

Given the previous 4 week return to baseline, they chose 6 weeks for Phase 2, giving an extra 50% safety margin to ensure return to baseline. Unfortunately (or very fortunately for patients) the return to baseline for this version was prolonged and invalidates some of the study.

The longer a clinical study goes on, the higher the chance you have of patients dropping out or going completely AWOL/no-contact. We have this issue in my work all the time - and we mostly deal with life saving surgical implants where the patient investment is so much greater than this trial, yet some still ghost us mid-trial. They either thought prolonging the washout to 12 weeks would incur high rates of dropouts, or the study funding just didn't stretch to accommodate that level of time. The 3 months is no issue as the study hasn't started at that point so they could have specified 12 months and it wouldn't have cost any additional money.

No clinical trial is perfect. Ever. It's easy for us to sit with the benefit of hindsight and say this and that was done wrong, but if it were me involved with this study, with the Phase 1 data in front of me, I'd sign off/approve these parameters for the Phase 2.

If the rationale given for this problem is truly unsatisfactory, the FDA will ask for additional work anyway to confirm Auricle's claims.

 

[gameover]

If the rationale given for this problem is truly unsatisfactory, the FDA will ask for additional work anyway to confirm Auricle's claims.

That's the nightmare I am afraid of.

They did this to Lenire (which of course was a sham). I guess there's a way to pay off FDA's buddies.

 

[Jonno02]

That's the nightmare I am afraid of.

They did this to Lenire (which of course was a sham). I guess there's a way to pay off FDA's buddies.

For medical devices, the regulator is there to ensure patient safety. Auricle do have (supposed) clinical proof the device works and has no major side effects.

I'm not a Regulatory Affairs expert, but I'd be surprised if any additional work was requested.

 

[BB23]

My tinnitus is partly somatic, but is non-tonal. I can't frequency match at all! It sounds and feels like electricity shooting around inside my skull.

My question is:

I'm being "treated" using a binaural beats track. It is supposed to consist of many different tones, not just one, playing all at once.

If we can't make sure of the frequency of our tinnitus, can something like that be done using this device as well, as in, can we play multiple tones of different frequencies at the same time just to make sure we are hitting the right tinnitus frequency/frequencies (i.e., a tone at 8 kHz, another at 11 kHz, another at 15 kHz, or various narrowband tones all at the same time)?

 

[dj_newark]

My tinnitus is partly somatic, but is non-tonal. I can't frequency match at all! It sounds and feels like electricity shooting around inside my skull.

My question is:

I'm being "treated" using a binaural beats track. It is supposed to consist of many different tones, not just one, playing all at once.

If we can't make sure of the frequency of our tinnitus, can something like that be done using this device as well, as in, can we play multiple tones of different frequencies at the same time just to make sure we are hitting the right tinnitus frequency/frequencies (i.e., a tone at 8 kHz, another at 11 kHz, another at 15 kHz, or various narrowband tones all at the same time)?

Dr. Shore addresses this in the Q&A. I hope this helps!

Do you need to be able to match your tinnitus tone to use the device? What if you don't have a stable tinnitus tone, but e.g., electrical noises, crickets, screeching, or multiple tinnitus tones in various frequencies? Can all these different tones and/or sounds be treated at the same time? Does the treatment work better for a certain kind of tinnitus, such as tonal high frequency?

The TinnTester interactive tinnitus matching software program is designed to match different kinds of tinnitus and has shown high test-retest reliability. Most tinnitus is narrow band or wide band, meaning it is comprised of multiple frequencies – called the tinnitus spectrum. We matched the tinnitus spectrum and presented this as the sound part of the bisensory stimulus. We did not see differences based on spectrum.

 

[UKBloke]

It's easy for us to sit with the benefit of hindsight and say this and that was done wrong

I do understand that and yes I would agree if we were picking at a couple of minor points, but an entire arm of a clinical trial has been invalidated.

The comment you made about them not knowing how long-lasting the effects of other treatments would be seems reasonable. But even with the addition of a 50% safety margin at crossover that still doesn't address how they were so unprepared for what transpired.

I agree that no trial is perfect but what I'm being asked to accept is that after 20 years' development a clinical team (presumably) made some changes to a device setting between one study and the next and unwittingly trebled (Dr. Shore's assertion) the longevity of its effect. I'm not quite ready to take that at face value just yet.

 

[Jonno02]

I do understand that and yes I would agree if we were picking at a couple of minor points, but an entire arm of a clinical trial has been invalidated.

The comment you made about them not knowing how long-lasting the effects of other treatments would be seems reasonable. But even with the addition of a 50% safety margin at crossover that still doesn't address how they were so unprepared for what transpired.

I agree that no trial is perfect but what I'm being asked to accept is that after 20 years' development a clinical team (presumably) made some changes to a device setting between one study and the next and unwittingly trebled (Dr. Shore's assertion) the longevity of its effect. I'm not quite ready to take that at face value just yet.

I suppose it's all sort of inconsequential now anyway. We're at the stage now that it's a 'it works or doesn't' as we're waiting for regulatory submission.

Phase 2 does indeed have some unanswered questions and the publication really should have gone into detail about why the issues happened with Group 2 rather than just 'washout wasn't long enough.' I agree.

Two studies that show it does work to some extent make me think this treatment will be effective, but as for how effective... that'll come with user reviews, I guess.

As a side question, does anybody else feel like they'd be 'immune' to a placebo? I constantly check the volume of my tinnitus in regular settings, and I feel like I'd be able to detect a reduction straight away rather than just a 'I think it's quieter... maybe.' I've done all the supplements etc that we all try and never once thought they helped in the slightest.

 

[Nick47]

As a side question, does anybody else feel like they'd be 'immune' to a placebo? I constantly check the volume of my tinnitus in regular settings, and I feel like I'd be able to detect a reduction straight away rather than just a 'I think it's quieter... maybe.' I've done all the supplements etc that we all try and never once thought they helped in the slightest.

I think most of those with severe tinnitus that have had the condition for years are much less likely than newbies or chronic mild-moderate cases to experience placebo.

Really, this is what disappointed me with Dr. Shore's study, and tinnitus studies in general. TFIs knocking around the 30-50 range and lots of of patients recruited have had the condition for 6-12 months.

I understand why they recruit at moderate, not severe levels, sure. But it's the severe cases that require treatment the most. Plus, like you said, the researchers may shoot themselves in the foot with placebo effects.

 

[2noist]

I understand why they recruit at moderate, not severe levels, sure.

Why do they do that in general?

 

[Nick47]

Why do they do that in general?

They are looking for more stable levels of tinnitus and want to eliminate co-morbid anxiety, depression, etc. Plus, severe cases may also be on medications that contraindicate the trials.

 

[tiniturk]

I do want to have an informal conversation with the person who thought it would be good idea to go to a rock concert while he or she was in the trial, lmao. I love irresponsible people.

 

[BB23]

I wonder if Dr. Shore's device can help with the vibration sensations too. I'm on top of my game with the potassium channel openers but this device is not very easy to figure out...

 

[diesal11]

I do want to have an informal conversation with the person who thought it would be good idea to go to a rock concert while he or she was in the trial, lmao. I love irresponsible people.

I think it's silly on surface but it's really useful data. I'd love to know if they attended the concert with hearing protection or not. If not, and the treatment is this fragile to loud environments with hearing protection, it will rule out a large cohort of sufferers who have tinnitus because of loud work environments.

I am kind of confused, can you sum it up for me why people are complaining about the coding language to begin with? Did they not get a software engineer involved in the development?

It's written in a dead programming language which presents issues if it's a requirement for the treatment, but FWIW, I'm also in the "it's not remotely an issue" camp and I apologise if I caused alarm for anyone, as others have said, it's really common for research code to look like this.

I also think this kind of app could relatively easily be rewritten for another platform; the actual TinnTester process isn't overly complex, it's just made near impossible to port due to how difficult it can be to guarantee output volume levels from computers. But recently, I found this problem has already been kinda solved by Apple on iOS with their ResearchKit framework. They've contributed some code that allows for an Audiometry test using iPhone + AirPods, within this code is a calibration file of sorts for each AirPods model, that allows the developer to calculate more precise dB output levels. I'm pretty sure this same calibration file can be used to calculate the values used for TinnTester.

 

[Muggumbo]

I wonder if Dr. Shore's device can help with the vibration sensations too. I'm on top of my game with the potassium channel openers but this device is not very easy to figure out...

I believe the vibration sensation can come from the harshness of certain pitches since I get this sometimes when mine acts up. Dr. Shore did say in the Q&A that some patients did get a softening of their tones so I believe it's possible.

 

[Joshyboy]

I wonder if Dr. Shore's device can help with the vibration sensations too. I'm on top of my game with the potassium channel openers but this device is not very easy to figure out...

Which ones? XEN1101 for neuromuscular inflammatory tinnitus?

 

[BB23]

Which ones? XEN1101 for neuromuscular inflammatory tinnitus?

XEN1101 is the only one with the potential to help, BHV-7000 is not as strong. There isn't anything else in the pipeline as of now.

 

[UKBloke]

how difficult it can be to guarantee output volume levels from computers.

I know this is slightly off-topic but that's an interesting point. When listening to podcasts (especially those with multiple participants), I've often found myself wishing there was a way to just normalise the volume coming out of the laptop. When one participant speaks it can be so low that it's barely audible yet the next person opens their mouth and the loudspeaker practically parts your hair. That Apple iOS wotsit you mentioned - have they found a way to deal with that problem?

@dj_newark, I just re-read my latest replies to you. Apologies if I came across a bit terse. That wasn't my intention!

 

[dj_newark]

I know this is slightly off-topic but that's an interesting point. When listening to podcasts (especially those with multiple participants), I've often found myself wishing there was a way to just normalise the volume coming out of the laptop. When one participant speaks it can be so low that it's barely audible yet the next person opens their mouth and the loudspeaker practically parts your hair. That Apple iOS wotsit you mentioned - have they found a way to deal with that problem?

@dj_newark, I just re-read my latest replies to you. Apologies if I came across a bit terse. That wasn't my intention!

Thanks, I appreciate that. I was not aware of the fact that there was no requirement to avoid other tinnitus treatments during the washout period. I wasn't aware of that, so thanks for bringing that to my attention. It seems common sense that no one would seek other tinnitus treatment during the washout phase, but as we all know common sense isn't common, so yes that probably should have been spelled out in the requirements for the trials.

 

[Travis Henry]

Do you think Dr. Shore's device will help reactive tinnitus, loudness hyperacusis, and noxacusis? How about Visual Snow Syndrome?

Will it help people with zero sound tolerance regain a life outside of hiding in a closet?

 

[Muggumbo]

Do you think Dr. Shore's device will help reactive tinnitus, loudness hyperacusis, and noxacusis? How about Visual Snow Syndrome?

Will it help people with zero sound tolerance regain a life outside of hiding in a closet?

Time will tell. It'd be nice if people could soon just get the damn thing in their hands so everyone can find it out themselves.

 

[IYIiKe]

I think it's important both to have hope and a mild skepticism. I know for some Dr. Shore's device is it, but even from that recent presentation people are already questioning how to improve upon it. Perhaps these additional devices will spur competition and a sense of urgency.

Unfortunately, like Dr. Dirk de Ridder has said, a lot of treatments have shown plausible efficacy but not clinical significance. Insurance companies won't pay out without clinical significance, and that is a barrier to treatment for many without means to try experimental methods.

Personally, I am more interested in Dr. Shore's device and other electrical stimulation as a lot of literature points to hyperactivity of the DCN in my subset of tinnitus. I would love nothing more than to unscramble such a condition and I am hopeful there will be more meaningful science-backed treatments in the future.

 

[Daphne91]

Is it the case that around this time next month (end of Q1) we should be able to check the FDA's open database to see if the device has been submitted for approval?

 

[Jason Cohen]

I know for some Dr. Shore's device is it, but even from that recent presentation people are already questioning how to improve upon it.

What presentation?

 

[Pixelito]

I think it's important both to have hope and a mild skepticism. I know for some Dr. Shore's device is it, but even from that recent presentation people are already questioning how to improve upon it. Perhaps these additional devices will spur competition and a sense of urgency.

Unfortunately, like Dr. Dirk de Ridder has said, a lot of treatments have shown plausible efficacy but not clinical significance. Insurance companies won't pay out without clinical significance, and that is a barrier to treatment for many without means to try experimental methods.

Personally, I am more interested in Dr. Shore's device and other electrical stimulation as a lot of literature points to hyperactivity of the DCN in my subset of tinnitus. I would love nothing more than to unscramble such a condition and I am hopeful there will be more meaningful science-backed treatments in the future.

The bottom line is no matter how many people attempts to question or devalue the clinical trials, it worked for more patients than it didn't. And for others, it reduced their ringing. When the device is used in real-world applications for longer periods than the limited testing in clinical trials, there is every reason to believe the percentages of success are going to increase exponentially.

I believe when all is said and done, the number of people who receive absolutely no benefits from the device is going to be a very small minority.

And subsequently, who knows what upgrades or improvements will be made based on the initial run of the device?