AM-101 Clinical Trial — Q&A

AM-101 Clinical Trial Q&A

The questions were answered by three investigators who participated in the AM-101 Phase 3 trials

• Kenneth Maxwell, MD, Winston-Salem, USA
• Tony Cox, MD, Hasselt, Belgium
• Guido Mühlmeier, MD, Ulm, Germany

and Auris Medical.


Mechanism of Action

Why does AM-101 help since it is known T is a brain issue in many cases? Of course T is related to hearing loss, but for me T is a brain issue (it calms down when taking brain meds). So I am wondering how this can be changed by injections into the ear.

Dr. Cox: The ear is connected to the brain by a nerve. In the majority of cases, the start of tinnitus is some abnormal signal which is generated by the ear and gets transmitted to the brain, using the nerve as a “highway” between the ear and the brain. Your ears can be damaged by sound and other types of trauma. It is like looking into bright light and developing blind spots in the eye. If there is any damage to the ear, there may be more of those abnormal signals going from the ear to the brain. By the nature of those abnormal signals, the brain puts more focus on it. In some instances, abnormal sensations can be blocked, for example, like using a local anaesthetic to block pain when you go to the dentist. The earlier you can bring down the abnormal sensory signals, the earlier you can prevent the brain from becoming fixated on this signal in the long-term. Once this process has occurred, it takes a longer time to heal. I often tell my patients that they need patience in order to achieve a large improvement in their long standing tinnitus. In the current clinical trials, we are investigating the effect of AM-101 in the down regulation of these abnormal sound signals in the early onset of tinnitus.


What about people for whom the cause of their tinnitus is unknown other than having been found to have some hearing loss. Is there a chance this treatment could help? Would it be available?

Dr Mühlmeier: Development of AM-101 is focusing on tinnitus triggered by traumatic insults (especially noise) to the inner ear or tinnitus triggered by middle ear infection. This is supported by results from animal experiments with noise trauma and by clinical data. While there are reasons to believe that the drug may work in other types of tinnitus as well, the only way to find out will be by further testing. In one of the Phase 2 trials, the drug was tested in patients suffering from tinnitus following some acute hearing loss without any known cause. Overall, there was no treatment effect observed – but in quite a few study participants, there were clear signs of efficacy. So the jury is still out on this.


Eligibility

• Accepting patient with tinnitus onset of more than 3 month?
• Any chance helping chronic Tinnitus? In their web site they are talking about Tinnitus which is up to a year – why is the trial only for 3 months? Can chronic tinnitus with recent noise exposure and increase in tinnitus loudness be helped?
• Is there any plans for Canada to go past the under 3 month trial?
• I have just now passed the 3 month mark of having Tinnitus. Is it too late to be considered for the trial?

Auris Medical: AM-101 is currently being developed for the treatment of tinnitus in the acute stage, which is defined as up to 3 months from onset. At this stage, tinnitus from traumatic injury to the inner ear or from otitis media is expected to be still an inner ear problem that may be treated locally. Beyond the acute stage, it is possible that tinnitus may get centralized in the brain – which may imply that a local treatment to the inner ear becomes less effective or no more effective at all. When exactly such centralization happens, and in whom, is not fully understood. In order to explore how far the therapeutic time window for AM-101 extends, we are enrolling in our European trial (TACTT3) also cases of post-acute tinnitus in addition to cases of acute tinnitus – i.e. up to 6 months from onset. The outcomes from this particular patient group will be analyzed separately. An interim analysis that was conducted after enrolment of the first half of post-acute tinnitus patients suggested that AM-101 could indeed be active also in the post-acute stage, and in particular up to 6 months.


Can AM-101 help people whose Tinnitus may have been caused by a Sinus infection?

Dr Maxwell: This is an interesting question. The current Phase 3 clinical trials are evaluating tinnitus due to acute trauma to the inner ear or middle ear infection. AM-101’s effect on tinnitus due to sinus infections has not yet been studied. It is possible that a sinus infection may spread to the middle ear and finally also affect the inner ear. But this would need to be tested first before we can say whether it is useful or not.


Any way to become part of the clinical trial if you're from Sweden?

Auris Medical: Unfortunately, there are no study sites in Sweden, and there is no possibility to participate in another country where the trial is running due to the different languages and logistical issues.


Injections related

How many injections [are given] in phase 3? For example, is it 1 injection every 3 weeks for a total of 4 times, or something similar?

Dr Cox: There are 3 injections, given over 3 to 5 days. Each study participant is followed up for 3 months. At the conclusion of the study, he/she may then take the option to join the open-label extension study. It is possible to take up to 3 treatment cycles in the open-label study, each with 3 injections over 3 to 5 days and a follow-up period of 3 months afterwards.


Is it really medically safe to perforate the eardrum multiple times? What are the possible complications?

Dr Maxwell and Dr Mühlmeier: Puncture of the eardrum has been performed in adults and children for many years. It has been used for injecting other drugs into the middle ear, and some of them require multiple treatments. Another common use is for the insertion of ventilation tubes (grommets) into children’s ears. Some children require repeated sets of ventilation tubes, resulting in their eardrums being punctured multiple times. In our experience, multiple punctures do not cause any long-term problems.

An eardrum perforation closes very quickly. If the ear is healthy and pressure can be cleared easily, the eardrum closes usually within 2 to 5 days. Before the eardrum is fully closed, the patient has to be careful not to get water into the ear as this may lead to middle ear infection. This risk of infection is very small. When the eardrum is not fully closed, a patient may experience distorted hearing, altered perception of tinnitus or pressure in the ear.


Side effects

Why do people report Tinnitus spikes? Are they common and can they be permanent or do participants say that it eventually settles down? The possibility of Tinnitus spikes is very scary.

Dr Mühlmeier and Dr Maxwell: In our experience, some study participants – but definitely not all! – experience some increase in tinnitus loudness after the injection. In the Phase 2 program with AM-101 this was reported by about 10% of study participants. This has been a temporary side effect in our clinics; none of the participating patients reported an increase that lasted longer than a week. You have to consider that part of the middle ear is filled with gel, and at the same time the eardrum has a small hole in it from the injection. This impacts how you are hearing – your ear may feel full, and sounds from the outside may appear a bit muffled, while your tinnitus may become more prominent as there is less sound coming in from the outside. Imagine putting your head under water – that changes sounds as well. Once the gel is gone and the eardrum fully closed again (normally this takes just a few days), this potential distortion to hearing and tinnitus is usually gone. We fully understand that if you have tinnitus you don’t want it to become louder. But consider this: there may be no “spike” at all, or only a small one, and if it happens that there is an increase in loudness, then it is a “mechanical” effect that will go away again rather quickly. From what we know based on earlier studies, the effect of AM-101 is gradual. So give it some time – the full effect is measured only 90 days after the study start!


Are the researchers confident that there will be no long-term side effects? I know the subjects in these trials responded well to the treatment in the 90 day trial period, but is there the possibility of side effects, let’s say, 5 or 10 years down the road?

Dr Mühlmeier: Esketamine, the active substance of AM-101, has been widely used for more than 15 years and in millions of patients for general anaesthesia. This is a safe drug. And these doses are even several hundred times higher than what is being used when administered as part of AM-101. The beauty of local administration is that you can have the drug delivered to where it is supposed to work without exposing the rest of the body. Last, but not least: the drug does not stay in the body for a long time, so I do not see from where long-term risks should come.


Unblinding and disclosure of results

I would like to know why a recipient will not be told if they received a drug or placebo at the conclusion of the initial study period, and before they enter into the off label study where verified real drug is administered. What is the harm when the initial study is completed to tell a trial participant they received the drug or placebo? If a participant received real drug and in the end found they did not benefit, then they should have this information to decide whether it is worth the risk of additional injections to continue on into the follow-up study.

Auris Medical: We appreciate that it is important for you to know which treatment you have received. However, these studies are conducted to support registration of AM-101 and there are strict rules on keeping the blinding on ALL patients until everyone has completed the study. This is done to prevent that knowledge of the type of treatment influences the outcome from the follow-on study. Auris Medical is committed to providing the treatment allocation to the investigators once the study has been completed and as soon as we are allowed to do so. Please note that participation in the follow-on study is optional; TACTT study participants may or may not continue. While the risks of the intervention are considered minor, there may be still some potential for benefiting from the active treatment in the AMPACT follow-on study.


So far, overall, how many people who have had the actual medication, saw a permanent decrease in their Tinnitus?

Auris Medical: Since we still remain blinded to the data in the current studies, we can only refer to past studies. On average, there was a gradual decrease in tinnitus loudness and tinnitus impact (annoyance, sleep disturbances, overall impact) over 90 days. In the past, we did not collect data beyond 90 days. However, based on anecdotal reports from study investigators and study participants we consider that the reduction was permanent. In some cases, patients were re-exposed to loud noise some time after exiting the study and reported that their tinnitus had become louder again. Hence it is important to protect ears whenever they are at risk!

In the current Phase 3 program with AM-101 we are collecting a large amount of data beyond the first 90 days; this will provide us with additional insights into the time pattern of effects.


Future

Seeing [it] as a lot of people I think that the 'cure' for tinnitus will be multi-faceted, is there a possibility that the drug/injection might be more beneficial if used in conjunction with another drug? Will it be possible that this possibility might be researched in the future?

Dr Cox: Yes, you have made a good point, but it is not as simple as that. Tinnitus is partly due to central phenomena as previously mentioned. The peripheral and central nervous system is highly complex, and as we all know there is no single type of tinnitus. The cause and duration of the tinnitus vary a lot, and its intensity or impact on the patient is very different from patient to patient. Therefore there will most likely be different treatments and treatment approaches in the future. However, I believe that the way the patients cope with their tinnitus will always be very important in the long run.


When do you suppose this drug will be available on the market? In 1, 2 or 3 years?

Auris Medical: If all goes well, and the safety and efficacy of AM-101 is confirmed, Auris Medical plans to submit in 2016 an application for marketing authorization to the regulatory agencies of key countries. If approved, the drug may get marketed starting in 2017.


Questions from forum threads

Why do tinnitus loudness and tinnitus annoyance have to be rated so frequently when study participants would simply want to avoid being reminded of its presence?

Dr Cox: When I first learned about the daily rating, I had the same impression. After considering it further, I think it is a useful tool as a coping strategy. I often tell my patients that the way they think about tinnitus and how they cope with it is important for their long-term outcomes. I tell my patients that they don’t have to think about tinnitus all day long, but just before they go to bed honestly rate their tinnitus. Then go to bed and forget about it. The electronic system is just like a diary that records your tinnitus – don’t worry about the ups and downs, just give the rating as it is. Initially, it seems hard to do but in long run, you can consider it as a good exercise to learn how to cope with your tinnitus.


Is there any way to tell the difference between AM-101 and placebo?

Dr Maxwell: Absolutely not, it is not possible to tell the difference – neither for us investigators, nor for study participants. The gel looks exactly the same before it is injected, it flows the same way and it even tastes the same when swallowed. From all the safety data that have been accumulated so far, there is also no indication that the placebo or the active drug would have different side effects. I fully understand why many study participants are curious to know whether they got placebo or the active drug – and why people are tempted to compare their experiences with the first round of injections, where they do not know what they are receiving, with their experiences with further injections if they continue in the AMPACT study and then get the active drug for sure. However, the experience may be different for many other reasons – the second round is less of an unknown than the first one, expectations are already different, the injection process may be slightly different, etc. When I am asked about any placebo or active drug “hints” by my study patients, I always have to tell them that I cannot tell the difference.