The primary objective of this study is: * To assess the safety and tolerability of single ascending volumes of placebo as well as volumes and doses of AC102-suspension by intratympanic injection in healthy male and female subjects.The secondary…
ID
Source
Brief title
Condition
- Hearing disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety Endpoints:
* Treatment-emergent (serious) adverse events (TE(S)AEs)
* Treatment emergent adverse events of special interest (AESIs):
o Permanent sensorineural hearing loss
o Persistent conductive hearing loss
o Persistent tinnitus
o Persistent vestibular vertigo
o Persistent tympanic membrane perforation
o Infections of the outer, middle and inner ear
* Concomitant medication
* Clinical laboratory tests:
o Hematology
o Biochemistry
o Urinalysis
* Vital signs:
o Pulse rate (bpm)
o Systolic and diastolic blood pressure (mmHg)
o Body temperature
* ECG:
o Heart rate (HR) (beats per minute [bpm]), QTcF
Pharmacokinetic endpoints:
The following endpoints will be determined for AC102 by non-compartmental
analysis of the plasma concentration-time data:
* The area under the plasma concentration-time curve from zero to infinity
(AUC0-inf)
* The maximum plasma concentration (Cmax)
* The area under the plasma concentration-time curve from zero to t of the last
measured concentration above the limit of quantification (AUC0-last)
* The time to reach maximum plasma concentration (tmax)
* The terminal disposition rate constant (*z) with the respective half-life (t*)
* Other parameters, including apparent volume of distribution (Vz/F), apparent
total body clearance (CL/F), and other parameters as appropriate and possible,
as well as dose adjusted parameters, may be determined.
Secondary outcome
Not applicable
Background summary
AudioCure Pharma GmbH develops AC102
(6-fluoro-9-methyl-9H-pyrido[3,4-b]-indole) as novel pharmaceutical therapy for
the prevention and treatment of a range of hearing impairments with high unmet
medical need. The proposed clinical trial will be the first clinical
investigation with this new chemical entity and be performed in healthy
volunteers to be able to detect possible adverse effects that might be masked
by disease specific symptoms in patients.
The current focus of AudioCure*s development program for AC102 is on acute
hearing loss. Despite numerous efforts, to date, there are no approved
pharmacotherapies available for the treatment of Sudden Sensorineural Hearing
Loss (SSNHL). The treatment of hearing loss with systemic glucocorticoids,
which have anti-inflammatory and immunosuppressive properties, is recommended
in many countries. However, there is a lack of clear evidence for significant
beneficial effects of glucocorticoids therapy. Furthermore, such treatment
might not be justified due to the numerous possible side effects (e.g.
hypertension, osteoporosis, behavioral disturbances, diabetes).
The characteristic pathological feature of SSNHL is damage to the hair cells,
the sensory cells of the cochlea (located in the inner ear), and / or the
spiral ganglion neurons (SGNs) that comprise the auditory nerve. Inner and
outer hair cells are responsible for signal amplification and the conversion of
the acoustic stimulus into a neuronal signal that is transmitted by the
afferent SGNs to the central auditory system. Hair cells are the most
vulnerable elements in the cochlea. A crucial aspect of SSNHL is that neither
the hair cells nor the SGNs can be replaced once they are lost. Therefore, an
effective treatment of SSNHL requires fast and target-specific intervention in
order to avoid the acute hearing loss becoming a permanent condition (Raphael
et al., 2002).
The inner ear and the SGNs are well protected areas within the body and cannot
be reached easily by a systemically administered medication as it would have to
pass the blood-inner ear barrier and the blood-brain barrier. These barriers
prevent systemically taken drugs (e.g. orally) from reaching the inner ear at
concentrations sufficient to have a therapeutic effect. Increasing the dose
systemically to reach sufficient inner ear exposure may cause or enhance
systemic adverse reactions. To avoid this, drugs have to be delivered locally
into the middle ear by e.g. intratympanic (through the ear drum) injection.
From the middle ear, the drug can diffuse across the round window membrane
(RWM) into the inner ear. Intratympanic injections represent a routine
outpatient procedure for otolaryngologists.
Study objective
The primary objective of this study is:
* To assess the safety and tolerability of single ascending volumes of placebo
as well as volumes and doses of AC102-suspension by intratympanic injection in
healthy male and female subjects.
The secondary objectives of this study are:
* To determine single dose pharmacokinetics of intratympanically injected AC102
in healthy male and female subjects.
Study design
This is a multi center, open label, placebo-controlled, single dose escalating
study.
Each cohort will receive a single dose of placebo or AC102-suspension in an
ascending order.
Volume and/or dose escalation will only proceed following satisfactory review
of all available safety data.
Approximately up to 16 single-dose cohorts are planned (C1 to C12, n=3 subjects
per cohort). For the first (C1) and the fifth (C5) single-dose cohort, sentinel
dosing of 1 subject will occur approximately 2 weeks before dosing the
remaining 2 subjects.
The different cohorts may overlap, but always will a volume be evaluated first
using placebo only. It may be needed to pause escalation or to add another
cohort to confirm safety/tolerability data. The last cohort will be used to
repeat and confirm the optimal volume (= selected volume) and dose that were
selected based on the evaluation of all previous cohorts (safety/tolerability
and practicability of administration). Escalation steps and adaptations to the
proposed dosing regimen will be submitted for approval.
Intervention
Single intratympanic injection with study medication
Study burden and risks
Total of max. 6 visits, 2 days in hospital, blood draws, hearing tests, a
single injection in one ear, lifestyle restrictions.
The injection can be painful, a sense of pressure in the ear can be felt for a
short time, the volume of the injection can cause a temporary partial hearing
loss, vertigo that will pass quickly might occur, a small scar might remain in
the tympanum but this will not lead to hearing loss.
There is a very small chance on permanent perforation of the tympanum, a very
small chance on permanent hearing loss, a very small chance of damage to the
nerve affecting the sense of taste
Schlegelstraße 9
Berlin 10115
DE
Schlegelstraße 9
Berlin 10115
DE
Listed location countries
Age
Inclusion criteria
1. Signed Institutional Review Board (IRB) / Independent Ethics Committee (IEC)
approved informed consent form (ICF)
2. Willing and able to attend the trial visits
3. Able to read and understand trial documents and follow Investigator and
trial personnel instructions during visits, including audiology measurements
4. Female or male
5. Age * 18 years and * 40 years at the day of Screening
6. Body mass index (BMI) 18.0 - 30.0 kg/m2, inclusive, where BMI (kg/m2) <= body
weight (kg) / height2*(m2) at Screening Visit
7. Healthy as judged by a responsible physician with no clinically significant
abnormality identified on the medical or laboratory evaluation, including
12-lead ECG, vital sign assessment or physical examination
8. Normal age-related hearing in both ears according to DIN EN ISO 8253-1 and
DIN 7029:2017
9. Willing and able to use adequate hearing protection and to refrain from
engaging in activities or work involving loud noise exposure where sufficient
hearing protection is not possible or ensured for the duration of their
participation in this study
10. Willing and able to protect the ear canal and middle ear from water
exposure for as long as the tympanic membrane is not fully closed
11. A female volunteer must meet one of the following criteria:
* If of childbearing potential * agrees to use one of the accepted
contraceptive regimens from at least 28 days prior to until at least 30 days
after study medication administration. An acceptable method of contraception
includes at least one of the following:
a. Abstinence from heterosexual intercourse
b. Combined (contains estrogen and progestogen) hormonal contraception (oral,
vaginal, transdermal)
c. Progestogen only contraception (oral, injectable, implantable)
d. Intrauterine device
e. Intrauterine hormone-releasing system
f. Bilateral tubal ligation
g. Vasectomized partner
* If of non-childbearing potential * should be surgically sterile (i.e. has
undergone complete hysterectomy, bilateral oophorectomy, or bilateral tubal
ligation) or in a postmenopausal state (at least one year without menses at
Screening)
12. A male volunteer with sexual partners who are pregnant, possibly pregnant,
or who could become pregnant must meet the following criteria:
* Subject is unable to procreate, defined as surgically sterile (i.e. has
undergone a vasectomy at last 6 months before Screening)
* Subject agrees to use one of the accepted contraceptive regimens until 90
days after study medication administration. An acceptable method of
contraception includes one of the following:
a. Abstinence from heterosexual intercourse
b. Condom with spermicide.
Exclusion criteria
1. History of acute hearing loss from noise trauma, barotrauma or head trauma
in either ear at any time
2. History of idiopathic sudden sensorineural hearing loss in the past 2 years
3. Congenital hearing loss
4. History of chronic (> 6 months) noise exposure (for leisure or profession)
5. Chronic or acute tinnitus in either ear
6. Current vertigo/previous balance or vestibular disorders
7. Any clinically significant external or middle-ear pathology observed by
otoscopic examination or tympanometry (i.e. reduced mobility of the tympanic
membrane)
8. Any clinically significant abnormality of the tympanic membrane or the outer
ear canal in the selected ear that would preclude intratympanic administration
9. Absence of detectable OAEs in the frequency band with a concomitant
clinically significant increase in hearing thresholds in accordance with DIN EN
ISO 8253-1 and DIN 7029:2017
10. Known family history of hearing impairment, other than age related
11. History of autoimmune hearing loss, radiation-induced hearing loss,
fluctuating hearing, endolymphatic hydrops or Menière*s disease in either ear
12. History of chronic inflammatory or suppurative ear disease or cholesteatoma
13. Current evidence or history of acoustic neuroma or other retrocochlear
damage
14. History of otosclerosis
15. Suspected perilymph fistula or membrane rupture in either ear
16. Otitis media or otitis externa that is ongoing or ended within 30 days
prior to study treatment or is occurring several times per year
17. Radiation therapy in the head and neck area
18. Any therapy known as ototoxic (e.g. aminoglycosides [systemic or
ototopical], cisplatin, loop diuretics, quinine etc.)
19. Taking any anti-coagulant medication (direct oral anticoagulant [DOAC],
e.g. Apixaban®), vitamin K antagonists (e.g. Marcumar®), thrombocyte
aggregation blockers (e.g. Aspirin®) chronically or Aspirin® as a pain killer
acutely within one week before treatment
20. History or presence of drug abuse or alcoholism within the past 2 years
21. Positive urine screen of drugs of abuse (if not due to concomitant
medication, e.g. benzodiazepines as hypnotics) or alcohol breath test at
Screening or Day -1
22. Ingestion of alcohol within 48 hours prior to study medication
administration and during the in-house period.
23. Current smokers
24. Excess in xanthine consumption (more than 5 cups of coffee/day or
equivalent)
25. Subjects with diagnosed anxiety disorders, psychosis, depression,
schizophrenia, attempted suicide or other significant psychiatric conditions
that can impact their ability to cooperate and comply with the study protocol
26. Any clinically relevant autoimmune, respiratory, cardiovascular, hepatic,
gastrointestinal, renal, dermatological, neurological or other abnormality that
in the opinion of the Investigator may pose a safety risk to a subject in this
study, which may confound safety assessment, or may interfere with study
participation or the evaluation of study treatment
27. Known human immunodeficiency virus (HIV), hepatitis B or hepatitis C
infection
28. Having an active infection with SARS-CoV-2
29. Abnormal and clinically relevant laboratory results
30. Systemic steroids within the last three months (topical steroids like nasal
spray or cremes are allowed)
31. Seated pulse rate less than 45 beats per minute (bpm) or more than 100 bpm
at Screening or Day -1
32. Seated blood pressure below 95/55 mmHg at Screening or Day -1
33. Seated blood pressure higher than 150/90 mmHg at Screening or Day -1
(measurement may be repeated in 15 minutes if initial reading is believed to be
atypical for the subject)
34. Known congenital long QT syndrome or a corrected QT interval (QTc) using
Fridericia correction (QTcF) at Screening (QTcF > 450 msec for males and > 470
msec for females) or other clinically significant ECG abnormalities
35. Concurrent participation in another clinical study or participation in
another clinical study within 30 days or 5 half-lives of the experimental drug
(whichever is longer) prior to Screening Visit
36. Donation or loss of more than 450 mL blood during the 3 months before the
start of Screening
37. Women who are breast feeding, pregnant or plan to become pregnant during
the study or women of childbearing potential who are unwilling or unable to
practice an effective method of contraception
38. Subjects who are involved in the organization of the clinical investigation
or are in any way dependent on the Investigator or Sponsor
39. Major surgery within eight weeks before Screening or scheduled/planned
surgery within the time frame of the study
40. Legal incapacity or limited legal capacity.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2019-004969-40-NL |
| CCMO | NL72516.056.20 |