Safety, Tolerability and Efficacy for CGF166 in Patients With Unilateral or Bilateral Severe-to-profound Hearing Loss

Study Overview
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Brief Summary
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The goal of the study was to evaluate the safety, tolerability, and the potential ability of CGF166 delivered through IL-infusion to improve hearing. CGF166 is a recombinant adenovirus 5 (Ad5) vector containing a cDNA encoding the human Atonal transcription factor (Hath1).

Detailed Description
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This study evaluated the safety, tolerability, and potential efficacy of CGF166 and the associated delivery procedures in patients with severe-to-profound unilateral or bilateral hearing loss. Eligible patients were required to have documented, non-fluctuating hearing loss.

Official Title
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A Three-part, Multicenter, Open Label, Single Dose Study to Assess the Safety, Tolerability, and Efficacy of Intra Labyrinthine (IL) CGF166 in Patients With Severe-to-profound Hearing Loss

Conditions
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Unilateral Severe to Profound Hearing Loss OR Bilateral Severe to Profound Hearing Loss

Intervention / Treatment
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* Drug: CGF166


Participation Criteria
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Eligibility Criteria
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For all Parts A, B and C of the study, Inclusion criteria: Written informed consent must be obtained before any assessment is performed. For all Parts A, B and C of the study, male or female patients, 18 to 75 years old, inclusive, with severe-to-profound bilateral hearing loss or unilateral hearing loss with intact vestibular function in the nonoperative ear. Non-fluctuating severe-to-profound hearing loss is required for the study ear and is defined as: PTA within 10 dB of the PTA obtained at least 11 months previously. Word recognition within 20% of previous test at least 11 months previously Candidate ear (study ear): Minimal residual hearing based on the pure tone average of 0.5, 1, 2, and 4 kHz thresholds of ≤110 dB HL Candidate ear (study ear): Pure tone audiometric thresholds of ≥50 dB HL for each testable octave frequency of 0.125 and 0.250 kHz, ≥70 dB HL for each testable octave frequency from 0.5 through 8 kHz and sentence recognition scores ≤50% at screening. 6. Patients with intact vestibular function in at least one ear (non-study ear) as measured by vestibular evoked myogenic potential (VEMP) 7. Able to communicate well with the investigator, to understand and comply with the requirements of the study 8. MRI scan within 6 months or at screening to confirm suitability for inner ear surgery 9. Patients must weigh at least 40 kg to participate in the study, and must have a body mass index (BMI) <45 kg/m2. BMI = Body weight (kg) / [Height (m)]2 Exclusion Criteria: Patients with hearing loss caused by genetic/developmental disorders, e.g., cochlea aplasia Patients with existing conductive hearing loss or mixed hearing loss as judged by the Principal Investigator following a thorough review of all of the trial hearing assessments; Patients with a history of cochlear implant in the study ear Hearing loss due to any other cause that would not be expected to respond to hair cell regeneration, for example mechanical trauma or central auditory lesions or lack of an auditory nerve Patients who will require ototoxic drugs as routine therapy over the course of the study, for example cystic fibrosis patients Any contraindication to the planned surgery or anesthesia as determined by the surgeon or anesthesiologist Previous surgery in the study ear Any otological history, such as chronic otitis, cholesteatoma, tympanic membrane perforation, that suggests poor candidacy for cochlear implant or inner ear surgery or suggests potential interference with study auditory or vestibular function tests Pregnant women Abnormal vital signs and/or ECG that suggest potential contraindication for planned study anesthesia Past serious adverse reaction to anesthesia Meniere's Disease History of radiation therapy to the head and neck Participation in a clinical trial within the last 30 days Immunocompromised patients, as judged by the investigators based on patient history, physical exam and CBC

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CGF166 dose 20 uL<br>single dose volume #1 | Drug: CGF166<br>* CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion<br>|
| Experimental: CGF166 dose 30 and 40 uL<br>single dose volume #2 | Drug: CGF166<br>* CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion<br>|
| Experimental: CGF166 dose 40 uL<br>single dose volume #3 | Drug: CGF166<br>* CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion<br>|
| Experimental: CGF166 dose 60 uL<br>single dose volume #4 | Drug: CGF166<br>* CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion<br>|
| Experimental: CFG166 dose 30 uL<br>Single dose volume #5 | Drug: CGF166<br>* CGF166 is a recombinant adenovirus 5 (Ad5) vector containing the human Atonal transcription factor (Hath1) cDNA for administration via intra-labyrinthine infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Adverse Events | AE tables are below in the Adverse Events section of this report. | week 52 | 
| Number of Adverse Events | AE tables are below in the Adverse Events section of this report. | week 52 | 
| Summary of Pure Tone Audiometry in Treated Ear Compared to Pretreatment Values | Summary of pure tone audiometry air conduction thresholds at frequency 0.125 KHz | Days 29, 57, 85, 113, 141, 169, 358, 537, 600 | 
| Summary Pure Tone Audiometry Bone Conduction Thresholds in Treated Ear by Time and Frequency | Summary of pure tone audiometry bone conduction thresholds by time and frequency 0.250 KHz | Days 29, 57, 85, 113, 141, 169, 358,537, EoS | 
| Summary of Change From Baseline in Treated Ear's Pure Tone Audiometry Air Conduction Threshold by Frequency for Last Study Visit | Summary of change from baseline in pure tone audiometry air conduction threshold by frequency for last study visit is presented in table below. | Week 52 | 
| Summary of Change From Baseline in Non-treated Ear's Pure Tone Audiometry Air Conduction Threshold by Frequency for Last Study Visit | Summary of change from baseline in Non-treated ear's pure tone audiometry air conduction threshold by frequency for last study visit is presented in table below. | Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Change in Brainstem Auditory Evoked Responses (BAER) Compared to Pretreatment Values | BAERs was assessed with standard techniques for clinically significant threshold improvements compared to baseline levels. | 24 months | 
| Number of Participants With Response in Vestibular Function in Treated Ear Compared to Pretreatment Values | Response in vestibular assessments (Head impulse test (HIT), Vestibular evoked myogenic potential (VEMP), Subjective visual vertical (SVV)) to CGF166. | 24 months | 
| Number of Participants With Changes in Auditory Functions (Speech Recognition) and Vestibular Functions Before and After IL Infusion of CGF166 Between the Study Ear and the Contralateral Ear | Clinically signficant speech recognition improvement (word and/or sentence) following treatment. The individual auditory assessments were speech audiometry, AzBio sentence test, consonant nucleus consonant test, word recognition, Hearing-in-Noise Test (HINT), Brainstem auditory evoked response evaluations (BAER), Distortion product otoacoustic emission testing (DPOE) and shoebox audiometry. | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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gene therapy, unilateral hearing loss, bilateral hearing loss, balance, vestibular, cochlear implant, hearing restoration