Date: 2017-05-09
Type of
information: Results
phase: 3
Announcement: results
Company: Auris Medical (Switzerland)
Product: Keyzilen™ (AM-101)
Action
mechanism:
- NMDA receptor antagonist. AM-101 contains a small molecule that selectively blocks N-methyl-D-aspartate (NMDA) receptors. Emerging evidence suggests that NMDA receptors in the cochlea play a major role in the occurrence of tinnitus following inner ear excitotoxicity, which is characterized by excessive synaptic release of glutamate, the principal neurotransmitter in the auditory system. Cochlear excitotoxicity may be triggered by, for example, trauma (e.g. exposure to excessive noise), neuroinflammation, disturbances in inner ear blood supply, or the administration of certain ototoxic drugs. It has been hypothesized that the upregulation of NMDA receptors induced by cochlear excitotoxicity is responsible for aberrant excitation of auditory nerve fibres, which is perceived as tinnitus.
- The development of AM-101 is based on research conducted at the INSERM Institute for Neurosciences of Montpellier, France. The clinical development of AM-101 was initiated by Auris Medical in 2007. Patents have been granted in more than 30 countries worldwide to date.
Disease: acute peripheral tinnitus
Therapeutic
area: Otorhinolaryngology
Country: USA, Canada
Trial
details:
- The multi-centre, randomized, double-blind, placebo-controlled trial is designed to confirm the efficacy and safety of AM-101 (Esketamine gel for intratympanic injection) in the treatment of acute peripheral tinnitus following traumatic cochlear injury or otitis media. The TACTT2 study will enrol 330 patients aged 18 to 75 years at North American sites; all participants completing the study and continuing to meet certain criteria will be eligible to enter an open label safety study (AMPACT12) and receive up to 3 treatment cycles withM-101 over up to 9 months. (NCT01803646)
- AMPACT1 is the second of two open-label extension studies with Keyzilen® that were conducted in response to a request from the FDA for safety data from chronic intermittent use of Keyzilen® for up to 12 months. Participants who completed the TACTT2 trial were offered the option to roll over into AMPACT1, while still blinded to the treatment allocation. Patients were given the choice to receive up to three treatment cycles with each cycle comprising three intratympanic administrations of Keyzilen®, followed by a treatment-free observation period of 12 weeks. (NCT01934010)
Latest
news:
- • On May 9, 2017, Auris Medical announced key results from AMPACT1 (AM-101 in the Post-Acute Treatment of Peripheral Tinnitus 1), the open-label extension study of the Phase 3 TACTT2 clinical trial. The study provides additional confirmation on the long-term safety of Keyzilen® and suggests the potential for further therapeutic benefits from repeated treatment.
- TACTT2 and AMPACT1 were primarily conducted in North America. Patients enrolled in TACTT2 within three months from tinnitus onset, i.e. during the acute stage. Of the 316 patients who completed the TACTT2 trial, 257 patients rolled over into AMPACT1 and provided safety data; 228 of these patients provided exploratory efficacy data. At the time of enrollment into AMPACT1, all patients were in the post-acute stage.
- The primary safety endpoint of AMPACT1 was the incidence of clinically relevant hearing deterioration five weeks after the start of a treatment cycle. In line with the results from previous trials with Keyzilen®, such incidence was low (6%), with no signs of treatment-related effects. Over the course of AMPACT1, the hearing threshold at the average of 4, 6 and 8 kHz showed only little change. The vast majority of adverse events that were considered related to the study drug or treatment procedure were rated as either mild or moderate in intensity. Three patients experienced a total of four non-fatal, serious adverse events, none of which was considered related to the study drug. Confirming previous data, about 93% of tympanic membranes were already closed at the time of the first follow-up visit.
- Exploratory efficacy analyses of AMPACT1 show improvements in the Tinnitus Functional Index (TFI) as well as other tinnitus metrics. The TFI decreased on average by 8.2 points (95% confidence interval 6.2 to 10.1; baseline of 42.7 points) to the last follow-up visit. The more treatment cycles the patients received, the larger the reduction in the TFI was; the difference between three cycles and one cycle reached statistical significance. Similar results were achieved on subjective tinnitus loudness and tinnitus annoyance. In addition, 41% of AMPACT1 participants achieved a reduction in their tinnitus severity (extreme-severe-moderate-mild-none) by at least one grade and 28% reported that their tinnitus severity had improved "much" or "very much" compared to baseline.
- • On August 18, 2016, Auris Medical announced top-line results from the Phase 3 TACTT2 trial with Keyzilen™ (AM-101) in acute inner ear tinnitus. The TACTT2 trial did not meet the two co-primary efficacy endpoints of statistically significant changes in tinnitus loudness and tinnitus burden compared to placebo. Data from the TACTT2 trial support the positive safety profile established in previous studies, and results from the second Phase 3 trial, TACTT3, are expected in the fourth quarter of 2016.
The trial was conducted primarily in North America and randomized 343 patients to receive either Keyzilen™ 0.87 mg/mL or placebo in a 3:2 ratio. The co-primary endpoints were the improvement in subjective tinnitus loudness from baseline to Day 84 and the improvement in tinnitus burden from baseline to Day 84, measured by the Tinnitus Functional Index (TFI). Treatment with Keyzilen™ did not demonstrate a statistically significant difference in tinnitus improvement as compared to placebo for either endpoint. Keyzilen™ was well tolerated with no drug-related serious adverse events. The trial's primary safety endpoint, incidence of clinically meaningful hearing deterioration, was low with no statistically significant difference from the placebo group, supporting the safety profile of Keyzilen™.
• On March 30, 2016, Auris Medical announced the comletion of patient enrollment in the TACTT2 Phase 3 clinical trial of AM-101 in acute inner ear tinnitus. Top-line results from the TACTT2 trial are expected in August 2016. The TACTT2 trial, which is being conducted primarily in North America, is a pivotal, randomized, double-blind, placebo-controlled trial in acute inner ear tinnitus following traumatic cochlear injury or otitis media. More than 330 patients were randomized to receive either AM-101 0.87 mg/mL or placebo in a 3:2 ratio. The primary endpoints are the change in tinnitus loudness from baseline to Day 84 and the change in the Tinnitus Functional Index total score. The trial is being conducted under a Special Protocol Assessment with the FDA. The second Phase 3 clinical trial of AM-101, TACTT3, which is being conducted in Europe, will enroll approximately 300 patients during the acute tinnitus stage (Stratum A) and approximately 330 patients during the post-acute tinnitus stage (Stratum B). Auris Medical expects to complete enrollment of the TACTT3 trial in a few months.
- • On March 10, 2014, Auris Medical has announced enrollment of the first patient into the TACTT2 clinical trial. This phase 3 trial will evaluate the efficacy, safety and tolerability of intratympanic injections of AM-101 in the treatment of acute peripheral tinnitus following traumatic coch- lear injury or otitis media. TACTT2 will enroll 330 patients at more than 60 sites primarily in the United States and Canada.
- The initiation of the TACTT2 trial follows shortly after the start of TACTT3, its European counterpart. Both have been designed as pivotal double-blind, placebo-controlled trials and are part of Auris Medical’s phase 3 development program with AM-101. All participants completing one of the TACTT studies and continuing to meet certain criteria will be eligible to enter an open label safety study (AMPACT1, respectively AMPACT2)and receive up to three treatment cycles with AM-101 over up to nine months.
- • On November 4, 2013, Auris Medical has announced that it has reached agreement with the FDA under a Special Protocol Assessment (SPA) for its pivotal phase III trial with the investigational product AM-101 for the treatment of acute peripheral tinnitus. In parallel, Auris Medical will initiate a second, similarly designed phase III trial (TACTT31) and open label follow-on study (AMPACT22) in several European countries. The TACTT3 study will enrol 600 patients, of which 300 during the acute stage (up to 3 months from tinnitus onset) and 300 during the post-acute stage (4 to 12 months from tinnitus onset). Both TACTT studies are scheduled to start enrolment shortly.
Is
general: Yes
