We are glad to report that we have now received answers from Auris Medical regarding the Q&A that we organized earlier this month.
We would like to mention that the above is a result of the on-going efforts within Team Awareness.
We want to thank Auris Medical for being willing to partake in this effort!
AM-101 threads on Tinnitus Talk:
https://www.tinnitustalk.com/threads/am-101.366/
https://www.tinnitustalk.com/threads/am-101-tactt1-results-released.1994/
https://www.tinnitustalk.com/threads/am-101-participants-updates-and-q-a.6558/
Auris Medical Q&A
General comment: Due to data protection requirements Auris Medical can unfortunately not comment on individual requests or on study eligibility. The responsibility for subject enrolment into the ongoing clinical studies rests completely with the participating investigators.
Q: I'll ask a question I'm sure a lot of people will be asking - is there any known reason why AM-101 couldn't help those with long term tinnitus?
A: So far, AM-101 has been tested only in the acute stage, which according to some guidelines extends up to 3 months from onset. There is a certain consensus among experts that inner ear (peripheral) tinnitus may become centralized in some patients after the acute stage, which means that the target for a treatment may shift from the inner ear to the brain. However, the exact mechanism and timing of such centralization is unclear, and it must be noted that a considerable number of tinnitus sufferers will probably never experience any centralization at all. In the absence of reliable diagnostics to distinguish between peripheral and central tinnitus, we consider it prudent to explore AM-101's time window with a step-by-step approach. First, we need to demonstrate that AM-101 works in the acute stage and get it approved – in a second step, we will expand on this and seek to find out how far we can go. This is reflected by the design of our European trial, where we are testing AM-101 primarily in the acute setting, but in a separate stratum also in the post-acute setting (up to 12 months from onset).
Q: What, if any, do the results show for the AMPACT portion of the trials in terms of safety and effectiveness?
A: The AMPACT studies are still ongoing, results of these studies will be available and can be commented on only after they have been completed.
Q: Why are you carrying out trials in USA for only up to three months since onset of T and in Europe for up to three months and also from four months to 12 months?
A: The main objective of our Phase III trials is to confirm the efficacy and safety of AM-101 in patients whose tinnitus onset was within 3 months, in line with the target patient population assessed in Phase II. Thus, both the US and the European studies address primarily this patient population. Nevertheless, it is the intent to also obtain first exploratory data on the potential effect of AM-101 in patients with tinnitus onset beyond 3 months (up to 12 months), and this is therefore being addressed in the so-called Stratum B of the European study. Depending on the outcome of the latter, the company will decide whether further studies of AM-101 in patients with tinnitus older than 3 months are warranted.
Q: Why does there appear to be discrepancy between screening tests between different clinics in Europe and or USA?
A: The protocols foresee a minimum set of screening assessments, which are identical across countries throughout our global study programs. Nevertheless, different study sites may use different screening assessments to evaluate new patients as part of their own established routine. Auris Medical has no control over any additional screening assessments performed by different study sites, as long as the standards of the study protocols are maintained.
Q: As Auris Medical pay the out of pocket expenses to the trial clinics to pass on to the trialees in Europe... e.g., travel costs, hotel costs (if a long way from the trial centre), why does this differ from country to country? Surely this should be the same out of pocket expenses paid (up to a certain reasonable amount and relative to country costing in each country of course) across all the european countries including UK. So for example, in UK pay the travel costs plus the hotel costs but in France cant even get travel costs paid.
In USA totally different because the trialee is paid for participating in the trial up to 450 dollars I believe...
A: Patient reimbursements are handled differently from country to country because local legislations differ. Also, Ethics Committees (EU) and Institutional Review Boards (US) have different standards in different countries. Auris Medical is bound to adhere to the corresponding local standards and regulations.
Q: What are the chances of these injections actually making it worse for the trialee? It is very confusing? From the phase 2 trials it looks like there is a ten per cent chance that the injections can make the T worse for the participant? Is this correct? Is this what you study shows you? Or is this incorrect and in fact the injections are much safer than this?
A: As part of the safety assessments in Phase II, reports by patients of increased tinnitus loudness or severity were recorded as so-called "adverse events". Usually, this related to the opening of the eardrum and/or the presence of the drug product inside the middle ear and was resolved a few days later upon closure of the eardrum and as there was no longer any gel in the middle ear. This temporary effect of the procedure can be seen in Figure 3 of the publication by van de Heyning and colleagues (available on our website): tinnitus loudness on Day 1 and Day 2 (i.e. during the treatment phase) on average slightly increases before it starts to decrease. Think of how sound sometimes appears different during take-off in an airplane – there, the conduction of sound is impacted by changes in air pressure. Once you have cleared the ears, it is back to normal.
Q: How can you be sure that the injections are helping or can it be simple natural improvement or habituation?
A: In order to account for any spontaneous remission / natural improvement, it is standard for clinical studies to be conducted with patients randomized to receive either the active drug or a placebo. Therefore, in our ongoing studies all patients receive injections with the same gel formulation, but whereas for 60% of patients this gel will also contain the active ingredient, for the other 40% of patients the gel will be without the active ingredient (i.e. placebo). Furthermore, the studies are "blinded", meaning that neither the study physicians administering the injections nor the patients will know which of the two the patient receives. When analyzing the study data, a statistical analysis will be performed which compares the active treatment group against the placebo group, in order to account for any natural improvement.
Q: When will the AM-101 Phase 3 results be released to the public showing efficacy/non-efficacy in the 3 to 12 month t since onset group?
A: The results of the interim analysis on Stratum B (tinnitus onset between 3 and 12 months prior) will be analyzed by an Independent Data Monitoring Committee in March 2015, which will then issue its recommendation on whether recruitment should continue for Stratum B. The full results of Stratum B will be available in 2016, after the study has been concluded and the data have been analyzed.
Q: Is there a way to get me back on the trial? I chickened out first time and I wouldn't a second time, I promise. If so please contact me as I'd love to get back on them and since I've only had tinnitus 6 months now, when your product comes to market I'd never have another chance...What I'm saying have some compassion please.
A: Due to data protection requirements Auris Medical can unfortunately not comment on individual requests or comment on eligibility. The responsibility for subject enrolment rests completely with the participating investigators.
Q: How did AM-101 come about as a potential treatment? I'm really looking for a commentary around that "ah ha" moment... What lead them to it, etc.
A: The story of AM-101 began 2003 in Montpellier, a beautiful and vibrant university town in the south of France. There, a research group around Rémy Pujol and Jean-Luc Puel had spent many years uncovering the inner workings of the cochlea and the effects of cochlear injuries. Besides hearing loss, one of their key areas of interest had been tinnitus. They had first set up an animal model where rats were conditioned to jump onto a pole whenever an external sound was turned on. Once the animals were responding reliably to that stimulus, they were administered high doses of salicylate, the active dose of aspirin, which was known to provoke tinnitus. The French scientists observed that the animals now not only jumped onto the pole whenever there was that external sound, but also in silence. Obviously, the animals heard something very similar that made them jump – i.e. phantom sound or tinnitus. The next key step for the group was, and this is where the collaboration with Auris Medical started, to set up a model with real life tinnitus conditions. Salicylate leads only to short, transitory tinnitus, and there is no lasting damage to the cochlea. In fact, hardly any human being would ever suffer from permanent tinnitus following high-dose aspirin intake.
Matthieu Guitton, who had developed the earlier model as part of his Ph.D. thesis, set up a model where conditioned rats were exposed to a very loud pure tone for 15 minutes. The frequency of the traumatic sound was chosen in a way that maximum injury to the cochlea could be expected around the frequency of the sound that made the animals jump. The first "aha" moment occurred when the results of the experiments came out. There were 3 types of outcomes: one group of animals just kept on jumping when the external sound was presented, but not in the absence of the sound (i.e. no tinnitus), another group did jumps without the external sound during the first 24 to 48 hours, but after that it was back to normal (i.e. transitory tinnitus), and the last group kept on jumping with and without external sound (i.e. lasting tinnitus). This was amazing since this is also what happens in real life: if you expose 10 people of the same age and with comparable hearing to the same loud noise, some of them do not get any tinnitus at all, others just some short ringing in the ears, while the unfortunate ones get tinnitus for the rest of their life. The next "aha moment" came when animals were treated with AM-101 shortly before they were exposed to the loud noise. The experiments showed that now there were only two types of outcomes: either no tinnitus behavior at all, or just the transitory one – but no more lasting tinnitus. In other words: AM-101 suppressed the type of tinnitus that otherwise would stick around! Once we found further confirmation of AM-101's effect in another type of model, we knew that we were on to something very exciting and started the full development program.
Q: Is AM-101 (and AM-102 for that matter) considered a treatment only for those with tinnitus presumably caused by acoustic trauma?
A: We are currently testing AM-101 for its effects on tinnitus caused by acute acoustic trauma, barotrauma (excessive pressure changes from flying or diving), surgery related trauma or otitis media. We started our research with AM-101 in tinnitus triggered by acute acoustic trauma – here you can understand fairly well what is going on in the cochlea following a brief, heavy bout of noise exposure, and an animal model could be developed. For our first clinical trial in humans, we remained close to that model by recruiting soldiers suffering from tinnitus after acute acoustic trauma. In further clinical trials we expanded the criteria to include also barotrauma, surgery trauma and otitis media as onset factors – because the same mechanisms are at work as in acute noise trauma. There is an excessive release of glutamate, which in turn triggers so-called glutamate excitotoxicity – there is damage to sensory cells in the cochlea similar to what happens in stroke. There are various other types of traumatic or non-traumatic injuries to the cochlea where glutamate excitotoxicity is known or suspected to be involved. We therefore expect that AM-101 could work also in other types of tinnitus; but this remains to be confirmed by further testing.
Q: How do I qualify for a trial?
A: Please refer to the study website (www.tinnitus-study.info) as well as the study site physicians listed therein for details.
We would like to mention that the above is a result of the on-going efforts within Team Awareness.
We want to thank Auris Medical for being willing to partake in this effort!
AM-101 threads on Tinnitus Talk:
https://www.tinnitustalk.com/threads/am-101.366/
https://www.tinnitustalk.com/threads/am-101-tactt1-results-released.1994/
https://www.tinnitustalk.com/threads/am-101-participants-updates-and-q-a.6558/
Auris Medical Q&A
General comment: Due to data protection requirements Auris Medical can unfortunately not comment on individual requests or on study eligibility. The responsibility for subject enrolment into the ongoing clinical studies rests completely with the participating investigators.
Q: I'll ask a question I'm sure a lot of people will be asking - is there any known reason why AM-101 couldn't help those with long term tinnitus?
A: So far, AM-101 has been tested only in the acute stage, which according to some guidelines extends up to 3 months from onset. There is a certain consensus among experts that inner ear (peripheral) tinnitus may become centralized in some patients after the acute stage, which means that the target for a treatment may shift from the inner ear to the brain. However, the exact mechanism and timing of such centralization is unclear, and it must be noted that a considerable number of tinnitus sufferers will probably never experience any centralization at all. In the absence of reliable diagnostics to distinguish between peripheral and central tinnitus, we consider it prudent to explore AM-101's time window with a step-by-step approach. First, we need to demonstrate that AM-101 works in the acute stage and get it approved – in a second step, we will expand on this and seek to find out how far we can go. This is reflected by the design of our European trial, where we are testing AM-101 primarily in the acute setting, but in a separate stratum also in the post-acute setting (up to 12 months from onset).
Q: What, if any, do the results show for the AMPACT portion of the trials in terms of safety and effectiveness?
A: The AMPACT studies are still ongoing, results of these studies will be available and can be commented on only after they have been completed.
Q: Why are you carrying out trials in USA for only up to three months since onset of T and in Europe for up to three months and also from four months to 12 months?
A: The main objective of our Phase III trials is to confirm the efficacy and safety of AM-101 in patients whose tinnitus onset was within 3 months, in line with the target patient population assessed in Phase II. Thus, both the US and the European studies address primarily this patient population. Nevertheless, it is the intent to also obtain first exploratory data on the potential effect of AM-101 in patients with tinnitus onset beyond 3 months (up to 12 months), and this is therefore being addressed in the so-called Stratum B of the European study. Depending on the outcome of the latter, the company will decide whether further studies of AM-101 in patients with tinnitus older than 3 months are warranted.
Q: Why does there appear to be discrepancy between screening tests between different clinics in Europe and or USA?
A: The protocols foresee a minimum set of screening assessments, which are identical across countries throughout our global study programs. Nevertheless, different study sites may use different screening assessments to evaluate new patients as part of their own established routine. Auris Medical has no control over any additional screening assessments performed by different study sites, as long as the standards of the study protocols are maintained.
Q: As Auris Medical pay the out of pocket expenses to the trial clinics to pass on to the trialees in Europe... e.g., travel costs, hotel costs (if a long way from the trial centre), why does this differ from country to country? Surely this should be the same out of pocket expenses paid (up to a certain reasonable amount and relative to country costing in each country of course) across all the european countries including UK. So for example, in UK pay the travel costs plus the hotel costs but in France cant even get travel costs paid.
In USA totally different because the trialee is paid for participating in the trial up to 450 dollars I believe...
A: Patient reimbursements are handled differently from country to country because local legislations differ. Also, Ethics Committees (EU) and Institutional Review Boards (US) have different standards in different countries. Auris Medical is bound to adhere to the corresponding local standards and regulations.
Q: What are the chances of these injections actually making it worse for the trialee? It is very confusing? From the phase 2 trials it looks like there is a ten per cent chance that the injections can make the T worse for the participant? Is this correct? Is this what you study shows you? Or is this incorrect and in fact the injections are much safer than this?
A: As part of the safety assessments in Phase II, reports by patients of increased tinnitus loudness or severity were recorded as so-called "adverse events". Usually, this related to the opening of the eardrum and/or the presence of the drug product inside the middle ear and was resolved a few days later upon closure of the eardrum and as there was no longer any gel in the middle ear. This temporary effect of the procedure can be seen in Figure 3 of the publication by van de Heyning and colleagues (available on our website): tinnitus loudness on Day 1 and Day 2 (i.e. during the treatment phase) on average slightly increases before it starts to decrease. Think of how sound sometimes appears different during take-off in an airplane – there, the conduction of sound is impacted by changes in air pressure. Once you have cleared the ears, it is back to normal.
Q: How can you be sure that the injections are helping or can it be simple natural improvement or habituation?
A: In order to account for any spontaneous remission / natural improvement, it is standard for clinical studies to be conducted with patients randomized to receive either the active drug or a placebo. Therefore, in our ongoing studies all patients receive injections with the same gel formulation, but whereas for 60% of patients this gel will also contain the active ingredient, for the other 40% of patients the gel will be without the active ingredient (i.e. placebo). Furthermore, the studies are "blinded", meaning that neither the study physicians administering the injections nor the patients will know which of the two the patient receives. When analyzing the study data, a statistical analysis will be performed which compares the active treatment group against the placebo group, in order to account for any natural improvement.
Q: When will the AM-101 Phase 3 results be released to the public showing efficacy/non-efficacy in the 3 to 12 month t since onset group?
A: The results of the interim analysis on Stratum B (tinnitus onset between 3 and 12 months prior) will be analyzed by an Independent Data Monitoring Committee in March 2015, which will then issue its recommendation on whether recruitment should continue for Stratum B. The full results of Stratum B will be available in 2016, after the study has been concluded and the data have been analyzed.
Q: Is there a way to get me back on the trial? I chickened out first time and I wouldn't a second time, I promise. If so please contact me as I'd love to get back on them and since I've only had tinnitus 6 months now, when your product comes to market I'd never have another chance...What I'm saying have some compassion please.
A: Due to data protection requirements Auris Medical can unfortunately not comment on individual requests or comment on eligibility. The responsibility for subject enrolment rests completely with the participating investigators.
Q: How did AM-101 come about as a potential treatment? I'm really looking for a commentary around that "ah ha" moment... What lead them to it, etc.
A: The story of AM-101 began 2003 in Montpellier, a beautiful and vibrant university town in the south of France. There, a research group around Rémy Pujol and Jean-Luc Puel had spent many years uncovering the inner workings of the cochlea and the effects of cochlear injuries. Besides hearing loss, one of their key areas of interest had been tinnitus. They had first set up an animal model where rats were conditioned to jump onto a pole whenever an external sound was turned on. Once the animals were responding reliably to that stimulus, they were administered high doses of salicylate, the active dose of aspirin, which was known to provoke tinnitus. The French scientists observed that the animals now not only jumped onto the pole whenever there was that external sound, but also in silence. Obviously, the animals heard something very similar that made them jump – i.e. phantom sound or tinnitus. The next key step for the group was, and this is where the collaboration with Auris Medical started, to set up a model with real life tinnitus conditions. Salicylate leads only to short, transitory tinnitus, and there is no lasting damage to the cochlea. In fact, hardly any human being would ever suffer from permanent tinnitus following high-dose aspirin intake.
Matthieu Guitton, who had developed the earlier model as part of his Ph.D. thesis, set up a model where conditioned rats were exposed to a very loud pure tone for 15 minutes. The frequency of the traumatic sound was chosen in a way that maximum injury to the cochlea could be expected around the frequency of the sound that made the animals jump. The first "aha" moment occurred when the results of the experiments came out. There were 3 types of outcomes: one group of animals just kept on jumping when the external sound was presented, but not in the absence of the sound (i.e. no tinnitus), another group did jumps without the external sound during the first 24 to 48 hours, but after that it was back to normal (i.e. transitory tinnitus), and the last group kept on jumping with and without external sound (i.e. lasting tinnitus). This was amazing since this is also what happens in real life: if you expose 10 people of the same age and with comparable hearing to the same loud noise, some of them do not get any tinnitus at all, others just some short ringing in the ears, while the unfortunate ones get tinnitus for the rest of their life. The next "aha moment" came when animals were treated with AM-101 shortly before they were exposed to the loud noise. The experiments showed that now there were only two types of outcomes: either no tinnitus behavior at all, or just the transitory one – but no more lasting tinnitus. In other words: AM-101 suppressed the type of tinnitus that otherwise would stick around! Once we found further confirmation of AM-101's effect in another type of model, we knew that we were on to something very exciting and started the full development program.
Q: Is AM-101 (and AM-102 for that matter) considered a treatment only for those with tinnitus presumably caused by acoustic trauma?
A: We are currently testing AM-101 for its effects on tinnitus caused by acute acoustic trauma, barotrauma (excessive pressure changes from flying or diving), surgery related trauma or otitis media. We started our research with AM-101 in tinnitus triggered by acute acoustic trauma – here you can understand fairly well what is going on in the cochlea following a brief, heavy bout of noise exposure, and an animal model could be developed. For our first clinical trial in humans, we remained close to that model by recruiting soldiers suffering from tinnitus after acute acoustic trauma. In further clinical trials we expanded the criteria to include also barotrauma, surgery trauma and otitis media as onset factors – because the same mechanisms are at work as in acute noise trauma. There is an excessive release of glutamate, which in turn triggers so-called glutamate excitotoxicity – there is damage to sensory cells in the cochlea similar to what happens in stroke. There are various other types of traumatic or non-traumatic injuries to the cochlea where glutamate excitotoxicity is known or suspected to be involved. We therefore expect that AM-101 could work also in other types of tinnitus; but this remains to be confirmed by further testing.
Q: How do I qualify for a trial?
A: Please refer to the study website (www.tinnitus-study.info) as well as the study site physicians listed therein for details.
