Sensorineural Hearing Loss
Conditions
Keywords
Intratympanic Administration, Hearing Restoration
Brief summary
This is a phase 1/2 study of FX-322 at two dose levels compared to placebo in male and female adults otherwise healthy with stable sensorineural hearing loss.
Detailed description
Sensorineural hearing loss (SNHL) accounts for about 90% of all cases of hearing loss. The study will assess the safety of FX-322 (laduviglusib and sodium valproate) given as a single intratympanic injection in subjects with a medical history of sensorineural hearing loss that is associated with noise exposure or sudden hearing loss. Safety will be evaluated both systemically (lab and clinical monitoring) and locally (otoscopy and audiometry) in 24 subjects, and a blood PK profile of FX-322 will also be determined.
Interventions
DRUGFX-322
Intratympanic injection of FX-322 consists of laduviglusib and sodium valproate
DRUGPlacebo
Intratympanic injection
Sponsors
Frequency Therapeutics
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Adult aged 18-65 years. 2. Established diagnosis of stable sensorineural hearing loss (no changes of 10 dB or more at any frequency) by standard audiometric measures for \>6 months. 3. Documented medical history consistent with hearing loss being caused by noise exposure or sudden sensorineural hearing loss (documented audiogram at least 6 months prior to screening required). 4. Female subjects must be of non-childbearing potential or will need to utilize two methods of highly effective contraception during the study participation (e.g. hormonal contraception or an intrauterine device and condoms) or remain abstinent. Male subjects should use condoms with spermicide during the course of the study or remain abstinent. Subjects should not donate sperm or ova during the study period.
Exclusion criteria
1. Perforation of tympanic membrane or other tympanic membrane disorders that would interfere with the delivery and safety assessment of an intratympanic medication or reasonably be suspected to affect tympanic membrane healing after injection in either ear. This includes a current tympanostomy tubes. 2. Any conductive hearing loss of 10 dB or more at two or more frequencies in either ear. 3. A pure tone average of 70 dB or greater at 500Hz, 1000Hz, 2000Hz, and 4000Hz in the ear to be injected. 4. Active chronic middle ear disease or a history of major middle ear surgery, as an adult, in the ear to be injected. 5. Subject has had an intratympanic injection in either ear within 6 months of the screening visit. 6. History of clinically significant vestibular symptoms at the discretion of the investigator. 7. History of clinically significant systemic autoimmune disease (e.g. rheumatoid arthritis, Sjogren's syndrome, multiple sclerosis, psoriasis). 8. History of head or neck radiation treatment or exposure. 9. History of substance abuse within 2 years of the Screening Visit. 10. Positive urine pregnancy test or breast-feeding. 11. Any known factor, condition or disease that, in the view of the investigator, might interfere with treatment compliance, study conduct or interpretation of the results such as psychiatric disease or suicidal tendencies.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | Baseline through Day 90 | Treatment-emergent adverse events (TEAE) were defined as any untoward medical occurrence in a subject administered study drug that does not necessarily have a causal relationship with the treatment and were collected from the time of first dose through end of study (day 90). In particular, audiometric and otoscopic TEAEs were recorded per the American Speech-Language-Hearing Association (ASHA) guidelines. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cmax | Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose | Maximum concentration (Cmax) of FX-322 (Laduviglusib and Sodium Valproate) directly from individual concentration-time data |
| Tmax | Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose | Time to reach maximum concentration of FX-322 (Laduviglusib and Sodium Valproate) directly from individual concentration-time data |
| AUClast | Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose | Area under the concentration-time curve of FX-322 (Laduviglusib and Sodium Valproate) from time zero to the time of the last quantifiable concentration, calculated using the linear trapezoidal rule |
| t1/2 | Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose | The observed terminal elimination half-life of FX-322 (Laduviglusib and Sodium Valproate) |
| CL/F | Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose | Apparent total body clearance after extravascular administration of FX-322 (Laduviglusib and Sodium Valproate) |
Countries
United States
Participant flow
Recruitment details
23 participants who met all inclusion criteria and no exclusion criteria were enrolled at a single clinic site.
Pre-assignment details
23 participants were randomized into one of four treatment groups using a 1:1 allocation ratio for dose cohort (approximately 12 in each cohort) and a 2:1 allocation ratio for study drug (approximately 8 FX-322:4 placebo) within each cohort. Subjects received a single dose of FX-322L (0.05mL), FX-322H (0.2mL), or matching placebo.
Participants by arm
| Arm | Count |
|---|---|
| Placebo-Low Dose Single intratympanic injection of placebo into affected ear | 4 |
| Placebo-High Dose Single intratympanic injection of placebo into affected ear | 4 |
| FX-322 Low Dose Single intratympanic injection of FX-322 (laduviglusib 0.157mg/sodium valproate 4.43mg) into affected ear | 7 |
| FX-322 High Dose Single intratympanic injection of FX-322 (laduviglusib 0.628mg/sodium valproate 17.72mg) into affected ear | 8 |
| Total | 23 |
Baseline characteristics
| Characteristic | Placebo-Low Dose | Placebo-High Dose | FX-322 Low Dose | FX-322 High Dose | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 4 Participants | 7 Participants | 8 Participants | 23 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 2 Participants | 2 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 5 Participants | 6 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 4 Participants | 4 Participants | 6 Participants | 7 Participants | 21 Participants |
| Region of Enrollment United States | 4 participants | 4 participants | 7 participants | 8 participants | 23 participants |
| Sex: Female, Male Female | 2 Participants | 2 Participants | 2 Participants | 3 Participants | 9 Participants |
| Sex: Female, Male Male | 2 Participants | 2 Participants | 5 Participants | 5 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 4 | 0 / 8 | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 2 / 4 | 3 / 4 | 5 / 8 | 6 / 7 | 7 / 8 |
| serious Total, serious adverse events | 0 / 4 | 0 / 4 | 0 / 8 | 0 / 7 | 0 / 8 |
Outcome results
Primary
Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs)
Treatment-emergent adverse events (TEAE) were defined as any untoward medical occurrence in a subject administered study drug that does not necessarily have a causal relationship with the treatment and were collected from the time of first dose through end of study (day 90). In particular, audiometric and otoscopic TEAEs were recorded per the American Speech-Language-Hearing Association (ASHA) guidelines.
Time frame: Baseline through Day 90
Population: Safety Analysis Set = All subjects exposed to study drug and analyzed according to the actual treatment received regardless of the randomized treatment
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo-Low Dose | Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | 2 Participants |
| Placebo-High Dose | Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | 3 Participants |
| Pooled Placebo | Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | 5 Participants |
| FX-322 Low Dose | Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | 6 Participants |
| FX-322 High Dose | Number of Participants With Treatment-emergent Adverse Event(s) (TEAEs) | 7 Participants |
Secondary
AUClast
Area under the concentration-time curve of FX-322 (Laduviglusib and Sodium Valproate) from time zero to the time of the last quantifiable concentration, calculated using the linear trapezoidal rule
Time frame: Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose
Population: Pharmacokinetic Analysis Set = All subjects in the Safety Analysis Set with measurable plasma concentrations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-Low Dose | AUClast | AUClast of laduviglusib | 1.71 ng*hr/mL | Standard Deviation 0.766 |
| Placebo-Low Dose | AUClast | AUClast of sodium valproate | 2730 ng*hr/mL | Standard Deviation 2790 |
| Placebo-High Dose | AUClast | AUClast of laduviglusib | 3.52 ng*hr/mL | Standard Deviation 1.31 |
| Placebo-High Dose | AUClast | AUClast of sodium valproate | 13100 ng*hr/mL | Standard Deviation 4390 |
Secondary
CL/F
Apparent total body clearance after extravascular administration of FX-322 (Laduviglusib and Sodium Valproate)
Time frame: Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose
Population: Pharmacokinetic Analysis Set = Subjects in the Safety Analysis Set with plasma concentrations above the limit of quantification. Concentration-time data below the limit of quantification (BLQ) were treated as zero. The values of 4 of 7 subjects in the low dose group and 2 of 8 subjects in the high dose group were BLQ and were thus excluded from the PAS for CL/F as those values could not be calculated. The number analyzed for each data point below reflects quantifiable levels within in each group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-Low Dose | CL/F | CL/F of laduviglusib | 54.4 L/hr | Standard Deviation 9.93 |
| Placebo-Low Dose | CL/F | CL/F of sodium valproate | 0.510 L/hr | Standard Deviation 0.287 |
| Placebo-High Dose | CL/F | CL/F of laduviglusib | 147 L/hr | Standard Deviation 21.7 |
| Placebo-High Dose | CL/F | CL/F of sodium valproate | 0.788 L/hr | Standard Deviation 0.308 |
Secondary
Cmax
Maximum concentration (Cmax) of FX-322 (Laduviglusib and Sodium Valproate) directly from individual concentration-time data
Time frame: Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose
Population: Pharmacokinetic Analysis Set = All subjects in the Safety Analysis Set with measurable plasma concentrations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-Low Dose | Cmax | Cmax of laduviglusib | 0.62 ng/mL | Standard Deviation 0.191 |
| Placebo-Low Dose | Cmax | Cmax of sodium valproate | 345 ng/mL | Standard Deviation 94.9 |
| Placebo-High Dose | Cmax | Cmax of laduviglusib | 0.967 ng/mL | Standard Deviation 0.361 |
| Placebo-High Dose | Cmax | Cmax of sodium valproate | 767 ng/mL | Standard Deviation 309 |
Secondary
t1/2
The observed terminal elimination half-life of FX-322 (Laduviglusib and Sodium Valproate)
Time frame: Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose
Population: Pharmacokinetic Analysis Set = Subjects in the Safety Analysis Set with plasma concentrations above the limit of quantification. Concentration-time data below the limit of quantification (BLQ) were treated as zero. The values of 4 of 7 subjects in the low dose group and 2 of 8 subjects in the high dose group were BLQ and were thus excluded from the PAS for t1/2 as those values could not be calculated. The number analyzed for each data point below reflects quantifiable levels within in each group
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-Low Dose | t1/2 | t1/2 of laduviglusib | 2.58 hr | Standard Deviation 0.878 |
| Placebo-Low Dose | t1/2 | t1/2 of sodium valproate | 14.7 hr | Standard Deviation 3.86 |
| Placebo-High Dose | t1/2 | t1/2 of laduviglusib | 2.47 hr | Standard Deviation 0.28 |
| Placebo-High Dose | t1/2 | t1/2 of sodium valproate | 20.1 hr | Standard Deviation 2.93 |
Secondary
Tmax
Time to reach maximum concentration of FX-322 (Laduviglusib and Sodium Valproate) directly from individual concentration-time data
Time frame: Data points taken pre-dose and 0.5, 1, 2, 4, 8, 24 hours post-dose
Population: Pharmacokinetic Analysis Set = All subjects in the Safety Analysis Set with measurable plasma concentrations
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo-Low Dose | Tmax | Tmax of laduviglusib | 0.95 hr | Standard Deviation 0.206 |
| Placebo-Low Dose | Tmax | Tmax of sodium valproate | 2.88 hr | Standard Deviation 2.49 |
| Placebo-High Dose | Tmax | Tmax of laduviglusib | 1.63 hr | Standard Deviation 1.06 |
| Placebo-High Dose | Tmax | Tmax of sodium valproate | 2.38 hr | Standard Deviation 1.06 |