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Trial registered on ANZCTR


Registration number
ACTRN12621000749808p
Ethics application status
Not yet submitted
Date submitted
15/04/2021
Date registered
15/06/2021
Date last updated
15/06/2021
Date data sharing statement initially provided
15/06/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Pharmacokinetics and safety of intratympanic adenosine receptor ligands
Scientific title
Pharmacokinetics and safety of intratympanic adenosine receptor ligands in adults undergoing elective translabyrinthine resection of vestibular schwannoma
Secondary ID [1] 303967 0
None
Universal Trial Number (UTN)
U1111-1265-4238
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Hearing loss
 321583 0
Condition category
Condition code
Ear 319323 319323 0 0
Deafness

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This is a phase I/IIA study, examining the pharmacokinetics and safety of intratympanic delivery of adenosine receptor ligands. Two ligands, Regadenoson and Istradefylline, already FDA approved for separate clinical uses, have demonstrated efficacy in animal models in prevention of hearing loss associated with trauma and certain chemotherapeutics. Regadenoson has been approved for use as a pharmacological stress agent for radionuclide myocardial perfusion imaging. Istradefylline is used in Parkinson’s disease as adjunctive treatment to levodopa/carbidopa
The intervention is to place the adenosine ligand within the middle ear at the commencement of a long neurosurgical operation. During the operation for resection of a vestibular schwannoma, the inner ear is opened routinely. We are then able to sample the perilymph, to assess the penetration of the adenosine ligand through the round window into the desired site of action, without added morbidity to the patient. As the patient is under an anaesthetic and is closely monitored we will be able to assess any safety concerns.
The dosage will be determined by a clinical pharmacologist based on prior in-vitro as well as animal studies. The adenosine ligand will be prepared for topical application in a polaxomer 407 gel by a pharmacist. The topical application will be transtympanically by an ENT surgeon.
There are two adenosine ligands being studied, Istradefyline and Regadenoson. One of these will be randomly assigned to each patient.
Intervention code [1] 320277 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 327194 0
Incidence of adverse events as assessed by patient medical records.
Timepoint [1] 327194 0
48 hours post intervention
Secondary outcome [1] 394135 0
Establishing the pharmacokinetics of adenosine ligands delivered intratympanically, in particular its absorption through the round window into the perilymph
We will measure Cmax, Tmax, AUC, clearance and T1/2 for plasma and perilymph
Timepoint [1] 394135 0
Baseline, 30, 60, 120, 240 minutes post intervention

Eligibility
Key inclusion criteria
Patients undergoing elective translabyrithine resection of vestibular schwannoma
Minimum age
18 Years
Maximum age
99 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i. Unstable cardiac disease (Arrhythmias, recent MI/stent)
ii. Renal impairment (Creatinine >100 umol/L)

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Not applicable
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1 / Phase 2
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
5/07/2021
Actual
Date of last participant enrolment
Anticipated
3/07/2023
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
20
Accrual to date
Final
Recruitment outside Australia
Country [1] 23598 0
New Zealand
State/province [1] 23598 0
Canterbury

Funding & Sponsors
Funding source category [1] 308348 0
Charities/Societies/Foundations
Name [1] 308348 0
Eisdell Moore Centre
Country [1] 308348 0
New Zealand
Primary sponsor type
Charities/Societies/Foundations
Name
Eisdell Moore Centre
Address
22-30 Park Avenue, Grafton, Auckland, 1023
Country
New Zealand
Secondary sponsor category [1] 309167 0
None
Name [1] 309167 0
Address [1] 309167 0
Country [1] 309167 0

Ethics approval
Ethics application status
Not yet submitted
Ethics committee name [1] 308320 0
Health Research Council of New Zealand
Ethics committee address [1] 308320 0
Level 3 - ProCARE Building, Grafton Mews, at 110 Stanley Street (GPS: 50 Grafton Road), Grafton, Auckland 1010
Ethics committee country [1] 308320 0
New Zealand
Date submitted for ethics approval [1] 308320 0
25/06/2021
Approval date [1] 308320 0
Ethics approval number [1] 308320 0

Summary
Brief summary
Sensorineural hearing loss following chemotherapy or ear surgery is common and significantly impairs patients’ quality of life. A number of otoprotective agents have shown promise in animal models and the next step is to translate these into clinical use.
We have identified two otoprotective agents which act on the adenosine A2a receptor (A2AR) both of which are FDA approved and have established safety profiles. Istradefylline, used in Parkinson’s disease, reduces deafferentation of inner hair cells and improves the survival of afferent synapses after excitotoxic injury. Regadenoson, used as a cardiac stimulant in myocardial perfusion tests, also has strong anti-inflammatory effects in the cochlea.
Intratympanic administration of these drugs minimises any potential systemic side effects and provides adequate concentrations in the cochlea, especially the basal cochlea which is more susceptible to injury. Slow release of the drug within the middle ear permits better diffusion across the round window membrane. Poloxamer 407 gel has been used as a slow delivery vehicle both in animal studies and clinically. We plan to suspend the adenosine receptor ligands in this delivery vehicle.
We aim to study the pharmacokinetic properties of both of these agents. First, in vitro experiments will measure drug elution from the gel over time to establish peak drug concentrations and duration. Then in patients already having their inner ear opened we will deliver a trans-tympanic injection of these agents and measure both the perilymph and plasma levels at different time points to help establish therapeutic concentrations and safety profiles.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 110298 0
Dr Michael Bergin
Address 110298 0
Department of Otolaryngology Head and Neck Surgery, Christchurch Hospital, Private Bag 4710, Christchurch 8140
Country 110298 0
New Zealand
Phone 110298 0
+64 0276074601
Fax 110298 0
Email 110298 0
[email protected]
Contact person for public queries
Name 110299 0
Michael Bergin
Address 110299 0
Department of Otolaryngology Head and Neck Surgery, Christchurch Hospital, Private Bag 4710, Christchurch 8140
Country 110299 0
New Zealand
Phone 110299 0
+64 0276074601
Fax 110299 0
Email 110299 0
[email protected]
Contact person for scientific queries
Name 110300 0
Michael Bergin
Address 110300 0
Department of Otolaryngology Head and Neck Surgery, Christchurch Hospital, Private Bag 4710, Christchurch 8140
Country 110300 0
New Zealand
Phone 110300 0
+64 0276074601
Fax 110300 0
Email 110300 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant date underlying published results only
When will data be available (start and end dates)?
The data will be retained for 10 years post the conclusion of the study. We aim to recruit till 03/07/23 and thus data will be available from then till 03/07/33.
Available to whom?
Data will be available to researchers only who provide a methodologically sound proposal
Available for what types of analyses?
Only to achieve the aims of the approved proposal
How or where can data be obtained?
The data will be retained by the primary investigator on a password protected personal computer. Contact with the leadinvestigator (Michael Bergin at [email protected]) requesting the data will thus need to be obtained


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
11377Study protocol    381810-(Uploaded-15-04-2021-19-23-57)-Study-related document.pdf



Results publications and other study-related documents

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