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

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

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).

Study Overview

• Status: Completed
• Conditions: Unilateral Severe to Profound Hearing Loss OR Bilateral Severe to Profound Hearing Loss
• Intervention / Treatment: Drug: CGF166

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • Novartis Investigative Site
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Novartis Investigative Site
  • New York
    • New York, New York, United States, 10032
      • Novartis Investigative Site
  • Oregon
    • Portland, Oregon, United States, 97239
      • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

For all Parts A, B and C of the study,

Inclusion criteria:

1. Written informed consent must be obtained before any assessment is performed.

2. 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
3. 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
4. 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:

1. Patients with hearing loss caused by genetic/developmental disorders, e.g., cochlea aplasia
2. 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;
3. Patients with a history of cochlear implant in the study ear
4. 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
5. Patients who will require ototoxic drugs as routine therapy over the course of the study, for example cystic fibrosis patients
6. Any contraindication to the planned surgery or anesthesia as determined by the surgeon or anesthesiologist
7. Previous surgery in the study ear
8. 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
9. Pregnant women
10. Abnormal vital signs and/or ECG that suggest potential contraindication for planned study anesthesia
11. Past serious adverse reaction to anesthesia
12. Meniere's Disease
13. History of radiation therapy to the head and neck
14. Participation in a clinical trial within the last 30 days
15. Immunocompromised patients, as judged by the investigators based on patient history, physical exam and CBC

Study Plan

How is the study designed?

Design Details

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

Number of Arms

5

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

General Publications

• Plontke SK. Otology Jubilee: 150 years of the Archiv fur Ohrenheilkunde "Where do we come from?--Where are we?--Where are we going?". Eur Arch Otorhinolaryngol. 2015 Jun;272(6):1301-3. doi: 10.1007/s00405-015-3538-4. Epub 2015 Feb 18. No abstract available.

Helpful Links

• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): June 23, 2014
• Primary Completion (Actual): December 9, 2019
• Study Completion (Actual): December 9, 2019

Study Registration Dates

• First Submitted: May 5, 2014
• First Submitted That Met QC Criteria: May 6, 2014
• First Posted (Estimate): May 7, 2014

Study Record Updates

• Last Update Posted (Actual): October 8, 2021
• Last Update Submitted That Met QC Criteria: October 7, 2021
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Keywords: vestibular; gene therapy; cochlear implant; balance; bilateral hearing loss; unilateral hearing loss; hearing restoration
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Otorhinolaryngologic Diseases; Ear Diseases; Sensation Disorders; Hearing Disorders; Hearing Loss; Deafness
• Other Study ID Numbers: CCGF166X2201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No