Clinical Trials

Date: 2017-09-22

Type of information: Completion of patient enrollment

phase: 3

Announcement: completion of patient enrollment

Company: Auris Medical (Switzerland)

Product: Keyzilen™ (AM-101)

Action mechanism:

• NMDA receptor antagonist. AM-101 is a small molecule N-methyl-D-aspartate (NMDA) receptor antagonist formulated in a biocompatible gel for intratympanic injection. 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 (anoxia/ischemia), or the administration of certain ototoxic drugs. It has been proposed 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 and comprises 3 clinical trials to date. Patents have been granted in more than 30 countries worldwide so far.

Disease: acute peripheral tinnitus

Therapeutic area: Otorhinolaryngology

Country: UE, USA

Trial details:

• TACTT3 is a randomized, placebo-controlled double-blind trial conducted in several European countries to evaluate AM-101 in the treatment of inner ear tinnitus following traumatic cochlear injury or otitis media. Participants in the TACTT3 trial receive three intratympanic injections of AM-101 0.87 mg/mL or placebo over three to five days and are followed for 84 days. (NCT02040194)
• AMPACT2 is one of two open-label extension studies with Keyzilen® that were conducted at the request of the FDA to generate safety data from chronic intermittent use of Keyzilen® for up to 12 months. Participants who completed the TACTT3 trial were offered the option to roll over into AMPACT2, 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. (NCT02040207)

Latest news:

• • On September 22, 2017, Auris Medical announced that it has completed the recruitment of patients for the Phase 3 TACTT3 clinical trial of Keyzilen® in acute and post-acute inner ear tinnitus. The trial enrolled more than 365 patients during both the acute tinnitus stage (Stratum A) and the post-acute tinnitus stage (Stratum B). Top-line results from the TACTT3 trial are expected in the first quarter of 2018.
• • 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 company also said that it expects to announce results from TACTT3, the European placebo-controlled sister trial to TACTT2, in early 2018. The trial has been extended to recruit an additional 60 patients in each of the acute and post-acute strata (i.e. up to three months and between three and six months from onset), and enrollment is ongoing.
• • On April 24, 2017, Auris Medical announced key results from AMPACT2 (AM-101 in the Post-Acute Treatment of Peripheral Tinnitus 2), the open-label extension study of the Phase 3 TACTT3 clinical trial. The study confirms the long-term safety of Keyzilen® and further supports early treatment from onset of inner ear tinnitus. Of the approximately 660 patients enrolled in the TACTT3 trial up to June 2016, 485 patients rolled over into AMPACT2 and provided safety data; 422 of these patients provided exploratory efficacy data. At the time of enrollment into AMPACT2, all patients were in the post-acute stage; approximately half were from Stratum A (originally enrolled in TACTT3 during the acute stage; i.e. up to three months from onset) and the other half were from Stratum B (originally enrolled during the post-acute stage; i.e. between three and 12 months from onset).
• The primary safety endpoint of AMPACT2 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, amounting to 4-8% with no significant difference between one, two or three treatment cycles. During the course of AMPACT2, the patients' hearing threshold at the average of 4, 6 and 8 kHz was stable. 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. Seven patients experienced a total of eight non-fatal, serious adverse events, none of which was considered related to the study drug. Confirming previous data, 96-98% of tympanic membranes were already closed at the time of the first follow-up visit.
• Exploratory efficacy analyses of AMPACT2 show improvements in the Tinnitus Functional Index (TFI) that were more pronounced for Stratum A patients compared to Stratum B patients. For Stratum A patients, the TFI decreased on average by 7.6 points (95% confidence interval 5.5 to 9.6; baseline of 40.3 points) to the last follow-up visit. For Stratum B patients, the TFI decreased on average by 3.5 points (1.4 to 5.6; baseline of 42.3 points) when enrolled in TACTT3 between three and six months from onset and by 2.5 points (-1.1 to 6.1; baseline of 45.3 points) when enrolled in TACTT3 between six and 12 months from onset.
• Auris Medical expects to announce results from AMPACT1, the open-label extension study related to TACTT2, later this quarter. TACTT3 has been extended to recruit an additional 60 patients in each of Stratum A and B, and enrollment is ongoing; top-line results are expected in early 2018. As recruitment for AMPACT2 has completed, the open-label extension is not offered to patients currently enrolling in the extended TACTT3 trial.
• • On January 26, 2017, Auris Medical announced that it has resumed patient enrollment in the TACTT3 Phase 3 trial of Keyzilen® (AM-101) in acute and post-acute inner ear tinnitus. TACTT3 previously enrolled more than 300 patients during the acute tinnitus stage (Stratum A) and approximately 330 patients during the post-acute tinnitus stage (Stratum B).
• • On December 6, 2016, Auris Medical confirmed that the TACTT3 Phase 3 trial with Keyzilen™ (AM-101) will resume enrollment in early 2017 as per previous guidance. This announcement follows receipt of key approvals from regulatory agencies and ethics committees in Europe on the recently submitted TACTT3 protocol amendment. The amended protocol elevates the Tinnitus Functional Index score from a key secondary endpoint to an alternate primary efficacy endpoint, includes certain patient subgroups in confirmatory statistical testing and increases the trial size with the enrollment of an additional 120 patients.
• As part of the Company's continued dialogue with the FDA, Auris Medical recently had two meetings related to the Keyzilen™ program. Through a Type C Meeting, the FDA confirmed that, as per standard practice, two positive confirmatory trials would be required to submit a New Drug Application (NDA); the Agency did not provide feedback on the TACTT3 protocol amendment because the trial is being conducted in Europe and is not under the Investigational New Drug Application. In a separate meeting with the FDA, alignment was achieved on key items of the Keyzilen™ Chemistry, Manufacturing, and Controls section for a future NDA.
• • On October 11, 2016, Auris Medical announced additional clinical data as well as updates to its development plan for Keyzilen™ (AM-101) in acute inner ear tinnitus. Based on insights from the recently completed TACTT2 trial, Auris Medical is submitting a protocol amendment to regulatory agencies in Europe for TACTT3, the ongoing second Phase 3 clinical trial.
• In the amended trial protocol, the change in Tinnitus Functional Index (TFI) score will be elevated from a key secondary endpoint to an alternate primary efficacy endpoint. Certain patient subgroups will be included in confirmatory statistical testing, and the trial size will be increased to enhance statistical sensitivity to the effects of treatment. Top-line results from the expanded TACTT3 trial are now expected in early 2018. The outcomes from TACTT2 and the regulatory path forward will be reviewed with the FDA in early December 2016.
• TACTT2 failed to meet its two co-primary endpoints: the change in subjective tinnitus loudness (tinnitus loudness question; TLQ) and the change in tinnitus burden measured by the TFI from baseline to Day 84 over placebo. However, the data show treatment effects on TFI in favor of Keyzilen™ for specific subgroups. In the pre-specified subgroup of patients suffering from tinnitus following otitis media, treatment with Keyzilen™ resulted in a clinically meaningful and statistically significant reduction of 14.8 points in the TFI from baseline, as compared to 6.2 points for placebo (p=0.048). A reduction of 13 points was defined as clinically meaningful by the developers of the TFI. A trend for improvement was also observed in active-treated patients who suffered from severe or extreme tinnitus at baseline with a clinically meaningful reduction in TFI of 15.5 points as compared to 11.5 points in the placebo group (p=0.238). Unexpectedly, the TLQ showed a lower sensitivity to change than the TFI, which the Company believes to be related to the frequent (daily) rating of tinnitus loudness over an extended period of time.
• So far, TACTT3 enrolled more than 300 patients during the acute tinnitus stage (Stratum A) and approximately 330 patients during the post-acute tinnitus stage (Stratum B). Under the amended trial protocol, the change in tinnitus loudness and in the TFI from baseline to Day 84 will both be alternate primary efficacy endpoints. Applying the Hochberg procedure, the two endpoints will be tested for the overall study population as well as for the subpopulations of patients with otitis media-related tinnitus or with severe tinnitus at baseline. In order to enhance the trial's statistical power, 60 additional patients will be recruited in TACTT3 in each of Stratum A and Stratum B. Auris Medical expects enrollment to resume in early 2017.
• • On June 28, 2016, Auris Medical announced that it has completed patient enrollment in the Phase 3 TACTT3 clinical trial with Keyzilen™ (AM-101) in acute and post-acute inner ear tinnitus. Top-line results from the TACTT3 trial are expected in the fourth quarter of 2016. The trial has enrolled more than 300 patients during the acute tinnitus stage (Stratum A) and approximately 330 patients during the post-acute tinnitus stage (Stratum B). The primary endpoint is the change in tinnitus loudness from baseline to Day 84. The change in the Tinnitus Functional Index, which measures tinnitus burden, is a secondary efficacy outcome.
• • On March 10, 2015, Auris Medical announced the completion of the planned interim analysis in the post-acute tinnitus stratum of the TACTT3 trial ("Stratum B") with AM-101 and that enrollment could continue since the pre-specified futility threshold was not reached. Based on recommendations by the Independent Data Review Committee, the inclusion criteria will be adapted in order to focus on the early post-acute stage where higher levels of activity were observed than at the later stage. Accordingly, Stratum B will continue to enroll patients with tinnitus having started between 3 and 6 months prior and stop enrollment of patients with onset 6 to 12 months prior. The TACTT2 trial and Stratum A of TACTT3, which enroll patients with tinnitus up to 3 months from onset and were not part of the interim analysis, will continue unchanged.
• The interim analysis on Stratum B of the randomized, double-blind, placebo-controlled European TACTT3 trial was performed based on 150 study participants (50% of the planned total) completing their second follow-up visit on Day 35. Futility was assessed since AM-101 had never before been tested beyond the acute stage of tinnitus (up to 3 months from onset). The evaluation was based on the primary efficacy variable of the trial, improvement in subjective tinnitus loudness, as well as on improvement in the Tinnitus Functional Index.
• • On January 14, 2015, Auris Medical announced that it has enrolled the first 150 patients with post-acute tinnitus in Stratum B of its ongoing TACTT3 clinical trial, representing fifty percent of the target enrolment in this Stratum.  Stratum B of the TACTT3 trial is enrolling patients in the post-acute tinnitus stage (between 3 and 12 months from onset), whereas Stratum A is recruiting patients with acute tinnitus (up to 3 months from onset). While previous clinical trials with AM-101 had focused on acute tinnitus only, data from a Phase 2 trial suggested that AM-101 might be effective also beyond the three month acute stage. Stratum B is seeking to explore if and to what extent AM-101 could be effective in the treatment of post-acute tinnitus. A planned interim analysis for futility will be performed once the enrolled 150 Stratum B participants will have completed their second follow-up visit on Day 35. As previously indicated, no interim analysis is planned for Stratum A, and enrollment is expected to be completed in fall 2015.
• • On February 21, 2014, Auris Medical has announced enrollment of the first patient into in the TACTT3clinical trial - a phase 3 study designed to evaluate the efficacy, safety and tolerability of intratympanic injections of AM-101 in the treatment of acute peripheral tinnitus following traumatic cochlear injury or otitis media. The TACTT3 study will enroll 600 patients at more than 60 European sites: 300 during the acute tinnitus stage (up to 3 months from onset) and 300 during the post-acute tinnitus stage (4 to 12 months from onset). • On November 4, 2013,  Auris Medical has announced that the company 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. The company has also reached agreement with the FDA under a Special Protocol Assessment (SPA) for its pivotal phase III trial with AM-101 for the treatment of acute peripheral tinnitus.

Is general: Yes