New University of Michigan Tinnitus Discovery — Signal Timing

[IntotheBlue03]

Final Study completion date moved forward from June to April.

Estimated Primary Completion Date: April 2022
Estimated Study Completion Date: April 2022

Thanks! @InNeedOfHelp, just curious where you saw this?

 

[ajc]

Thanks! @InNeedOfHelp, just curious where you saw this?

It's on the ClinicalTrials.gov page for the trial:

https://clinicaltrials.gov/ct2/show/NCT03621735

 

[IntotheBlue03]

It's on the ClinicalTrials.gov page for the trial:

https://clinicaltrials.gov/ct2/show/NCT03621735

Excellent, so for those of us not too familiar with clinical trials, that means we may potentially get those study results by sometime in April/May?

 

[ajc]

that means we may potentially get those study results by sometime in April/May?

Unlikely. It will take them a couple of months to process and publish the results.

Dr. Shore is blinded to the results until April, at which time she will get access to the results and can start analyzing them before eventual publication later this year, maybe summer/autumn.

 

[InNeedOfHelp]

Excellent, so for those of us not too familiar with clinical trials, that means we may potentially get those study results by sometime in April/May?

The primary and secondary data will be available to the researchers in April. Usually within 1-2 months a first press release is given with preliminary results, the actual publication will follow months later.

The FDA timelines for a class 1 or 2 non-invasive medical device approval is 3-6 months.

 

[Uklawyer]

If I could, I'd jump on them if preliminary results were good. I would have thought that they had a portal for participants to record their experiences which could then be inputted somewhere to generate results numerically and graphically pretty quickly. Is that not likely?

 

[IntotheBlue03]

Excellent, thank you both @InNeedOfHelp @ajc
for this input. I know this is just rumor mill at this point but again for those of us who are not familiar with the overall process this is helpful.

I'm assuming that FDA approval could not be undertaken (I've seen talk in this thread regarding "fast tracking" and am unsure what that entails) until the publication or preliminary results are released?

 

[ThomasRobert]

The primary and secondary data will be available to the researchers in April. Usually within 1-2 months a first press release is given with preliminary results, the actual publication will follow months later.

The FDA timelines for a class 1 or 2 non-invasive medical device approval is 3-6 months.

Is there any FDA Calendar for upcoming "Medical Devices"?

 

[Gb3]

Excellent, so for those of us not too familiar with clinical trials, that means we may potentially get those study results by sometime in April/May?

I'm thinking like 2025.

 

[Jason Ranovik]

I'm a scientist (PhD) who has published a number of research papers, so I can shed some light on the process. Note that I'm not in the medical field though, so the process is surely a bit different.

The analytics/statistics that will be run on the data are defined in advance, i.e. they know before the study even starts how they will be processing the data once it's done. Or at least, they should be doing that for it to be a valid result (otherwise you get into "data mining" territory).

Given how hard and fast they seem to be pushing for the completion, my bet is that they already have the statistics software set up to be able to process the data as soon as it's unblinded. That's what I did for my studies: I created mock result data (randomly generated) that is in the same format as the final data would be, then wrote all the code to do the analysis and tested it, then as soon as the study was finished I would just load up the real result file and click "run". Since they're working with small data (less than several million data points), the analytics should complete literally in seconds. That's where they get the preliminary results from for a quick press release.

Writing up the paper is the much longer part, since you can't write the results and discussion sections until you have the actual results. However, I'd be shocked if they didn't have the majority of the paper already complete (intro, background, methodology, device design/characteristics, hypotheses, etc.), everything that they can write without knowing the final results.

Once the paper's ready, they might release a pre-print (non-peer-reviewed), might not. If they submit to a journal and wait for peer review before releasing anything, that's where the longest delay will be. The good news, though, is that I think the FDA process starts as soon as they submit their data to the FDA, it doesn't need to wait for the peer review process (someone correct me if I'm wrong on that).

So, my estimated timeline is:

• Late April: study complete
• Early May: results known (statistics/analytics complete)
• Late May: press release with preliminary results (which are the actual results, just not "official" since they're not yet published in a peer-reviewed journal)
• Early June: data submitted to FDA to start the approval process, and paper submitted to a journal
• August - October: paper published in a journal if it passes peer review
• End of 2022: device on the market in the US, assuming it actually showed significant results in the trial without any harmful effects

 

[IntotheBlue03]

I'm a scientist (PhD) who has published a number of research papers, so I can shed some light on the process. Note that I'm not in the medical field though, so the process is surely a bit different.

The analytics/statistics that will be run on the data are defined in advance, i.e. they know before the study even starts how they will be processing the data once it's done. Or at least, they should be doing that for it to be a valid result (otherwise you get into "data mining" territory).

Given how hard and fast they seem to be pushing for the completion, my bet is that they already have the statistics software set up to be able to process the data as soon as it's unblinded. That's what I did for my studies: I created mock result data (randomly generated) that is in the same format as the final data would be, then wrote all the code to do the analysis and tested it, then as soon as the study was finished I would just load up the real result file and click "run". Since they're working with small data (less than several million data points), the analytics should complete literally in seconds. That's where they get the preliminary results from for a quick press release.

Writing up the paper is the much longer part, since you can't write the results and discussion sections until you have the actual results. However, I'd be shocked if they didn't have the majority of the paper already complete (intro, background, methodology, device design/characteristics, hypotheses, etc.), everything that they can write without knowing the final results.

Once the paper's ready, they might release a pre-print (non-peer-reviewed), might not. If they submit to a journal and wait for peer review before releasing anything, that's where the longest delay will be. The good news, though, is that I think the FDA process starts as soon as they submit their data to the FDA, it doesn't need to wait for the peer review process (someone correct me if I'm wrong on that).

So, my estimated timeline is:

• Late April: study complete
• Early May: results known (statistics/analytics complete)
• Late May: press release with preliminary results (which are the actual results, just not "official" since they're not yet published in a peer-reviewed journal)
• Early June: data submitted to FDA to start the approval process, and paper submitted to a journal
• August - October: paper published in a journal if it passes peer review
• End of 2022: device on the market in the US, assuming it actually showed significant results in the trial without any harmful effects

THIS is amazing insight, thank you @Jason Ranovik!

 

[Uklawyer]

@Jason Ranovik, thanks for confirming what I already knew

But can you please rephrase your predicted timeline by stating "End of May 2022: device on the market in the US".

Thanks.

 

[DaveFromChicago]

To Jason Ranovik:

Thanks ever so much for posting exactly the type of impressive, professional information that motivates me to keep checking in.

The crucial point you made was "assuming it actually showed significant results in the trial without any harmful effects."

Jesus! Could it be true that we will be delivered from this within the year?

 

[IntotheBlue03]

I'm assuming that there were no adverse affects reported after the first clinical trial? I wasn't sure where to seek out this information but does anyone know? I know we are all holding our breath regarding the ratio of users who improved (60-65% I believe).

@AfroSnowman
@OptimusPrimed
@InNeedOfHelp
@Uklawyer
@Jason Ranovik

 

[AfroSnowman]

I'm assuming that there were no adverse affects reported after the first clinical trial? I wasn't sure where to seek out this information but does anyone know? I know we are all holding our breath regarding the ratio of users who improved (60-65% I believe).

@AfroSnowman
@OptimusPrimed
@InNeedOfHelp
@Uklawyer
@Jason Ranovik

No adverse effects were reported. Other than 3rd party reporting I'm not sure where the 60-65% responders number comes from. I would really suggest looking at the primary sources of information for answers and data, as reporters get stuff wrong, misunderstand, get sloppy, and have a primary interest in clicks not facts. The question of the percentage of responders was not something I saw in the paper, but maybe I looked through it.

 

[Gb3]

No adverse effects were reported. Other than 3rd party reporting I'm not sure where the 60-65% responders number comes from. I would really suggest looking at the primary sources of information for answers and data, as reporters get stuff wrong, misunderstand, get sloppy, and have a primary interest in clicks not facts. The question of the percentage of responders was not something I saw in the paper, but maybe I looked through it.

When @IntotheBlue03 bombarded Dr. Shore with emails, her research student said that.

 

[AfroSnowman]

When @IntotheBlue03 bombarded Dr. Shore with emails, her research student said that.

I thought someone said it came from a newspaper.

 

[IntotheBlue03]

Hey @AfroSnowman, forgive me for misquoting if I did, that figure came from another poster who later I believe changed it from 60-65%. No offense to anyone if I misread this.

 

[Padraigh Griffin]

Auditory-somatosensory bimodal stimulation desynchronizes brain circuitry to reduce tinnitus in guinea pigs and humans

Study results published from Phase 1 in detail if anyone wants to read or re-read.

Mean overall TFI scores decreased from baseline of 29.2±2.6 to 22.9±1.8 units during the active treatment, but remained unchanged during sham treatment. Improvements in TFI scores were sustained beyond the active treatment and into the washout period, unlike the changes in loudness matching. As treatment order also had no significant effect on TFI scores (GLMM; P=0.819), both groups were pooled for statistical analysis. The mean TFI scores across the different study periods were significantly improved (i.e., reduced relative to baseline) for both active and active washout periods (but not sham periods) (7.33±0.956 TFI units; two-way ANOVA, F(3,1)=7.712, P=6.14e-5) indicating a diminished impact on daily life with mean reductions of 7.51 and 6.71 points, respectively. Eleven participants noted subjective changes in volume, pitch, or quality that resulted in their tinnitus becoming less "harsh" or "piercing" and more "mellow." Even participants who did not experience a complete elimination of their tinnitus reported anecdotally that their tinnitus was noticeably less obtrusive and easier to ignore.

Ten of the 20 subjects had a clinically significant reduction of at least 13 points in their TFI scores during active treatment, which is considered clinically meaningful for this questionnaire. There were no demographic differences across subjects showing significant TFI changes compared to stable subjects. Four participants had clinically significant drops during the sham treatment, but two of these also showed significant decreases in TFI during the active treatment. Further, both participants reported that their tinnitus improved more during the active treatment. The two participants who stated that the sham treatment was more effective also had the shortest tinnitus duration (less than 1 year).​

There is no definitive data other than 50% had clinically significant decreases of 13 pts in TFI. We don't know their starting TFI. The mean was 28 pts. 10% had complete resolution. Tinnitus loudness reduced by close to that of a lightbulb humming for active group and the main point of interest is that results tended to peak at the end of treatment, therefore giving hope that prolonged treatment will achieve better results.

TFI scores were maintained in four week washout however loudness scores were not.

I think personally greater efficacy will be achieved with the extra 2 week period in Phase II, but I would like to see results for more severe TFI cases.

Another interesting point is that people who had had tinnitus for a lesser time period were the poorest responders.

The sample size was tiny though. Next trial results will be more conclusive.

 

[InNeedOfHelp]

I stated the 60%.

This was accurate, 12-13 out of 20 people responded, two had their tinnitus completely resolved. Reading again, im not sure if the 2 with completely resolved tinnitus where part of the 10 responders or not.

There is a difference between responding and clinically significant response though!


All participants went back to baseline tinnitus after the treatment though in db! TFI scores remained longer down but eventually also went to baseline. This is stated in the publication as well as interviews done with Shore after publication.

There was a cumulative effect seen, the more treatment the higher the impact (dB reduction). They are speculating that longer treatment will cause a more durable result, hence Phase 2 is now 6 weeks and groups with 30 minutes/day up to 60 minutes/day to define the best protocol.

See below graphs.

 

[InNeedOfHelp]

I'm assuming that there were no adverse affects reported after the first clinical trial? I wasn't sure where to seek out this information but does anyone know? I know we are all holding our breath regarding the ratio of users who improved (60-65% I believe).

@AfroSnowman
@OptimusPrimed
@InNeedOfHelp
@Uklawyer
@Jason Ranovik

Single stimulation caused adverse effects (increase in tinnitus) in mouse models, it was therefore crucial that the stimulation was done bi-modal.

No adverse affects were published (which I found odd quite frankly: listening to 30 minutes of sounds while having tinnitus distress sounds should create some anxiety or placebo increase at first).

 

[AfroSnowman]

Hey @AfroSnowman, forgive me for misquoting if I did, that figure came from another poster who later I believe changed it from 60-65%. No offense to anyone if I misread this.

No worries, I just think that is why it is important to just look at the actual study or other raw data when talking about this, everything else is at best a repeat of what is in the study or at worst an inaccurate representation.

 

[Watasha]

Unlikely. It will take them a couple of months to process and publish the results.

Dr. Shore is blinded to the results until April, at which time she will get access to the results and can start analyzing them before eventual publication later this year, maybe summer/autumn.

Do you really think that the results will be published within a year of the study ending? Serious question in case the tone is getting lost through text.

 

[ajc]

Do you really think that the results will be published within a year of the study ending? Serious question in case the tone is getting lost through text.

I expect peer-reviewed results be published in a journal sometime in 2023. The process & peer review always takes time. It's still faster than the incompetent people at Neuromod have been able to do...

But I'm 100% sure preliminary, key results will be announced in a matter of months after April. And Dr. Shore won't fuck us over like Neuromod did, that's the good thing about this being University research.

 

[IntotheBlue03]

Might be a silly question but having difficulty pouring over all the results and data. Thank you all for providing this.

Is there no data regarding the other 7-8 users who didn't have a clinically significant response? Wondering if they responded at all?

 

[DocTors_94]

I hope this device helps those with multitonal/non-tonal tinnitus too. It would be our salvation. Not sure if anyone here knows about this. Thank you.

 

[Brian Newman]

Yeah, I would love if it helped my 6 different tones calm down. Would be a relief. I wonder how this device will work for somebody with bad noxacusis. I get pain from little vibrations, so I wonder how the shocks will do.

 

[PeterPan]

So with your paragraph starting with "one other thing," are you saying Dr. Shore's device looks promising or not

It looks promising to me, and it will be very interesting to see the results later this year. It's a little strange that the original paper doesn't mention the technique used to ensure the participants weren't able to distinguish between the sham and treatment stages and the method of ensuring that this technique was effective (the answer to the first part is that in the treatment stage the electrical stimulation was at a level that participants reported as not detectable).

 

[Padraigh Griffin]

Is there no data regarding the other 7-8 users who didn't have a clinically significant response? Wondering if they responded at all?

That is all the data from Phase I. Phase II will be much more detailed and hopefully better results too.

 

[InNeedOfHelp]

I hope that they will go for FDA/EMA approval at the same time.

Lenire applied for FDA last July/August and still no update, while being available in Europe for two years now. Not a fan of Lenire but I certainly hope that worldwide commercialisation goes smoother for Auricle. I certainly do not hope we in Europe miss out on a possible treatment due to the lack of EMA submission...