Efficacy of AM 101 in Patients with Acute Inner Ear Tinnitus: A Multi-Centre, Double-Blind, Randomised, Placebo-Controlled, Multiple Dose, Group Comparison Phase II Study

Efficacy of AM 101 in Patients with Acute Inner Ear Tinnitus: A Multi-Centre,
Double-Blind, Randomised, Placebo-Controlled, Multiple Dose, Group Comparison
Phase II Study

Primary objective
The primary objective of the study is the evaluation of the therapeutic benefit
of three repeated dose intratympanic AM 101 injections in comparison to placebo
in the treatment of persistent acute inner ear tinnitus following acute otitis
media, acute acoustic trauma or sudden deafness.
Secondary objectives
The secondary objectives of the study are (a) safety and local tolerance of
intratympanically applied AM 101 and (b) identification of the optimal dose of
AM 101 in the treatment of persistent acute inner ear tinnitus from acute
acoustic trauma or sudden deafness.

This clinical trial is designed as a multicentre, double-blind, randomised,
placebo-controlled, multiple dose, group comparison phase II study.

After topical anaesthesia of the tympanic membrane, patients will receive an
intratympanic injection of 250 µl of study medication on D0. Following
injection they will rest for 30 minutes. On days D1 and D2 the procedure of
drug application will be repeated.
Patients will be randomized on D0 to receive either AM 101 270 µg/ml, AM-101
810 µg/ml, or placebo.
In case of bilateral tinnitus, only the ear with the higher tinnitus loudness
(as determined by loudness matching at 1 kHz) at baseline will be treated, or,
if equally loud, the ear with the greater hearing loss at 4 kHz will be
treated.

As of today, there exists neither a universal standard of care for tinnitus,
nor a truly proven, effective treatment method. Inner ear tinnitus may be short
and transitory, however, it may also become permanent and seriously impact the
ability to sleep, relax, or to concentrate, or lead to tiredness, irritation,
nervousness, despair, frustration, or depression.
Possible problems, risks for injuries or distress:
The pharmacology of Ketamine and Esketamine the API in AM-101 is well known,
and the drug has been in clinical use for a relatively long time already.
Ketamine is considered to have a good safety profile.
AM-101 had been tested in humans with intratympanic injection for the treatment
of acute inner ear tinnitus before. In the phase I/II clinical trial with
AM-101, all 4 doses - 30, 90, 270 and 810 ug/ml - were well tolerated and
showed no toxicities. The safety of the triple doses of 270 and 810 µg/ml,
which are to be administered in the phase II study, are considered to be safe
given the good safety profile observed in the previous clinical trial as well
as based on animal toxicology data. Repeated administration of Esketamine by
way of a 14 day continuous infusion onto the round window membrane of
guinea-pigs showed no toxicities even at 10 mg/ml respectively 2 mg in total
dose.
The treatment administration by intratympanic injection is a well established
and safe minimally invasive procedure and is usually well tolerated. The small
incision cicatrices rapidly. In very rare cases, local bleeding may occur into
the middle ear. Further, there may be infections in the middle ear. These
complications can be well treated or pass away spontaneously. The first
clinical trial with AM-101 confirmed the good safety of intratympanic
injections.
Ethical considerations:
It is planned to include a placebo to the control for spontaneous recovery of
hearing loss. A placebo design was chosen, as there is no proven standard of
care for the treatment of acute inner ear tinnitus. All patients, including the
participants receiving placebo (1 out of 3), benefit from close monitoring and
extensive medical care within the period of the study. All participants have
the opportunity to make a valuable contribution to inner ear tinnitus research.
Potential benefits for the patient
By participating in the phase II clinical trial, patients have a 2 in 3 chance
to get access to a new medicinal product and treatment method which may for the
first time ever provide effective relief from inner ear tinnitus. The phase
I/II clinical trial provided some first indications of potential efficacy of
the investigated medicinal product. Furthermore, all patients will get - free
of charge - comprehensive and intensive health care by specialists. Their
health, and in particular their hearing function, will be closely monitored.
Importantly, the provided medical care and attention will tend to decrease the
stress commonly related to tinnitus, which is known to potentiate the
perception of tinnitus. Thus also patients treated with placebo are likely to
benefit from participation in the trial.
Benefit/risk ratio:
The Sponsor considers risk/benefit ratio to be positive. AM-101 poses no
significant safety concerns for study participants, and offers at the same time
the potential for attenuation or suppression of acute inner ear tinnitus.