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Trial registered on ANZCTR


Registration number
ACTRN12615000657527
Ethics application status
Approved
Date submitted
1/05/2015
Date registered
25/06/2015
Date last updated
15/01/2016
Type of registration
Retrospectively registered

Titles & IDs
Public title
A Phase Ib, Randomised, Placebo-Controlled, Double-Blind Study to Evaluate Potential Benefits of Two Concentrations of Betahistine Dihydrochloride Spray Administered as a Single Intranasal Dose in Adult Male and Female Volunteers with Eustachian Tube Dysfunction
Scientific title
A Phase Ib, Randomised, Placebo-Controlled, Double-Blind Study to Evaluate Potential Benefits of Two Concentrations of Betahistine Dihydrochloride Spray Administered as a Single Intranasal Dose in Adult Male and Female Volunteers with Eustachian Tube Dysfunction
Secondary ID [1] 285986 0
Nil known
Universal Trial Number (UTN)
Trial acronym
OTI-BH-ETEAR-002
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Rhinitis 294475 0
Eustachian tube dysfunction 295379 0
Allergic rhinitis (hay fever) 295380 0
Condition category
Condition code
Ear 294782 294782 0 0
Other ear disorders
Inflammatory and Immune System 295640 295640 0 0
Allergies

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Site staff administer a single intranasal dose of two sprays in each nostril on two occasions on the same day, approximately 2 and a half hours apart; subjects are randomly assigned to receive either 4mg or 40mg of betahistine dihydrochloride, or placebo.
Intervention code [1] 291412 0
Treatment: Drugs
Comparator / control treatment
The placebo contains only the vehicle solution that the active drug is made up in. The placebo contains moisturising agents, buffers, preservatives, and water.
Control group
Placebo

Outcomes
Primary outcome [1] 294539 0
Tympanometry assessments. Changes in ear pressure are measured via a tympanometric headsets.
Timepoint [1] 294539 0
Measurements are automatically made approximately every 3 minutes for 2 hours post-dose
Secondary outcome [1] 313578 0
To assess the tolerability of BH spray at total exposures of 4 mg and 40 mg compared with placebo as assessed by adverse events experienced.
Timepoint [1] 313578 0
Baseline, 2 hours post-dose, 7 days post-dose and at any time reported by the subject.

Eligibility
Key inclusion criteria
1. Male or female volunteers aged 18 years or older.
2. History of rhinitis and perceived ET dysfunction as defined by self-reported difficulty in equalising ears during plane flights, particularly descent and a history of allergic rhinitis (hay fever), but otherwise healthy as assessed by medical history and physical examination.
3. Body mass index between 18 and 30 kg/m2 (inclusive).
4. Healthy as assessed by medical history and physical examination.
5. A female participant is eligible to participate if she is of:
a. Non-childbearing potential defined as (1) having a documented tubal ligation at least 6 weeks prior to dosing; (2) having had a surgical bilateral oophrectomy (with or without hysterectomy); (3) at least 12 months of spontaneous amenorrhoea with follicle stimulating hormone (FSH) > 40 mIU/mL.
b. Child-bearing potential with negative urine pregnancy test at screening and negative urine pregnancy test at check-in (Day 1), AND:
* Agrees to abstain from sexual intercourse, or to use condoms plus one other acceptable form of contraception; i.e. intra-uterine device, hormonal contraception, or a female diaphragm, from the time of dosing until 4 weeks after dosing with study drug.
* OR has only same-sex partners, when this is her preferred and usual lifestyle.
6. Male participants with female partners of childbearing potential must agree to use condoms for the duration of the study and until 4 weeks after dosing with the study drug.
7. Normal (Type A) tympanometric measurements at screening consistent with the normal healthy adult population. Type A is defined as follows: Ear canal volume between 0.8-1.8 mL, compliance greater than 0.3 mL but less than 1.6 mL, middle ear pressure between -100 daPa and +100 daPa.
8. Capable of providing written informed consent.
9. Able to comply with study procedures and follow instructions from staff.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
1. History or known presence of clinically relevant cardiovascular, pulmonary, gastrointestinal, hepatic, renal, metabolic, haematological, neurologic, psychiatric, systemic, ocular, or infectious disease; any acute infectious disease or signs of acute illness, especially of the ear, nose or throat (ENT) including “Swimmer’s Ear”.
2. History of spontaneous pneumothorax, known lung bullae disease or known extensive lung scarring (risk of pulmonary barotrauma)
3. Any history or presence of recurrent OME (including childhood history), myringotomy tubes (“grommets”), sinusitis, or known deviated nasal septum.
4. Presence of excessive cerumen (ear wax).
5. Positive pre-study test for alcohol or cotinine.
6. Presence or history of allergy to BH or any of the excipients or other allergy that, in the opinion of the investigator or Medical Monitor would compromise participation in the study.
7. Participant has received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
8. History of recurrent ENT infections, irritation or localised reaction to intranasally applied agents.
9. Recent history of liver disease, or known hepatic or biliary abnormalities with the exception of Gilbert’s syndrome or asymptomatic gallstones.
10. Females who are pregnant or breast-feeding.
11. Recent ENT surgery (within 3 months of screening).
12. History of bronchial asthma, gastric ulcers, or phaeochromocytoma.
13. History of migraines.
14. Use of prescription or non-prescription medications, vitamins, dietary or herbal supplements (including St John’s Wort) within 7 days prior to the dose of study drug unless in the opinion of the investigator and the Medical Monitor, the medication will not interfere with the study procedures or compromise participants safety.
15. Use of any cold and flu medication, antihistamine or nasal decongestants including but not limited to; Sudafed, Codral, Clarityne/Loratidine, Telfast, Drixine, etc within 7 days prior to the study dose.
16. A history of tobacco use in the last 3 months.
17. Current or history of symptomatic hypotension.
18. Any clinically significant deviation from normal in physical examination, vital signs or Electrocardiogram (ECG) beyond what is consistent with normal, healthy population.
19. Type As, Type Ad, Type B or Type C tympanometric measurements at screening and baseline as defined below:
a. Type A (not excluded): Ear canal volume in adults between 0.8-1.8 mL, compliance greater than 0.3 mL but less than 1.6 mL, middle ear pressure between -100 daPa and +100 daPa
b. Type As: shows same ear canal volume and middle ear pressure as Type A but the compliance (or peak) is equal to or less than 0.3 mL
c. Type Ad: shows same ear canal volume and middle ear pressure as Type A but the compliance (or peak) is equal to or greater than 1.6 mL
d. Type B: shows no measurable peak / middle ear compliance with any canal volume (low, normal or high)
e. Type C: shows a normal canal volume, a measurable peak, and middle ear pressure more negative than -100 daPa
20. A history of known hearing defects or tinnitus.
21. A participant who for whatever reason, in the opinion of the investigator, should not participate in the study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Participants who meet the inclusion/exclusion criteria will be assigned a randomisation numbers in the order of final eligibility for the study using a randomisation schedule generated prior to the start of the study. Participants will be randomly assigned to receive one of three treatments 4 mg of BH (low dose), 40 mg of BH (high dose), or placebo (1:1:1, i.e. 8 participants per treatment group). The Investigational Product is supplied by an off-site vendor labelled with the randomisation number but with no specification of the treatment included on the label.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated randomisation sequence
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 1
Type of endpoint(s)
Efficacy
Statistical methods / analysis
Demographics:
Demographic variables such as age, race, etc. and baseline status (medical history, physical exam, disease and treatment history, etc.) will be listed for each participant, and summarised by treatment group and overall, as applicable.
Safety and Tolerability:
All participants who have received a least one dose of IP will be evaluated for safety. Treatment-emergent AEs will be tabulated by participant and summarised per treatment group by count and proportion. AEs will be coded using the MedDRA dictionary. Incidence of AEs by the severity and relationship to treatment will be provided. Narratives of all SAEs will be included. ital signs and other safety parameters will be documented with the use of descriptive summary statistics. Physical examination data from baseline and Day 1 and medical history data at baseline will be listed. Laboratory values outside the laboratory’s reference ranges will be listed together with associated repeat values and comments as to their clinical significance. Individual profiles will be presented by participant for parameters with any clinically significantly abnormal values. Tolerability measures, including visual intranasal inspection, will be listed by participant and summarised by treatment group.
Pharmacodynamic parameters:
Descriptive statistics by treatment group will be calculated for all pharmacodynamics variables, including tympanometry evaluations, as measured values and changes over
time from baseline, where possible.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 3562 0
The Wesley Hospital - Auchenflower
Recruitment postcode(s) [1] 9369 0
4066 - Auchenflower

Funding & Sponsors
Funding source category [1] 290923 0
Commercial sector/Industry
Name [1] 290923 0
Otifex Therapeutics
Address [1] 290923 0
Otifex Therapeutics Pty Ltd
Level 9, 278 Collins Street
Melbourne VIC 3000
Country [1] 290923 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
Otifex Therapeutics
Address
Otifex Therapeutics Pty Ltd
Level 9, 278 Collins Street
Melbourne VIC 3000
Country
Australia
Secondary sponsor category [1] 289609 0
Commercial sector/Industry
Name [1] 289609 0
CPR Pharma Services
Address [1] 289609 0
28 Dalgleish Street
Thebarton SA 5031
AUSTRALIA
Country [1] 289609 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292528 0
UnitingCare Health Human Research Ethics Committee
Ethics committee address [1] 292528 0
UnitingCare Health Human Research Ethics Committee
The Wesley Hospital
PO Box 499
Auchenflower Qld 4066
Ethics committee country [1] 292528 0
Australia
Date submitted for ethics approval [1] 292528 0
28/10/2014
Approval date [1] 292528 0
09/01/2015
Ethics approval number [1] 292528 0
1426

Summary
Brief summary
This study is testing the potential benefits (if any) of betahistine dihydrochloride when administered as an intranasal spray (via the nose) to Eustachian tube function. This study involves a total of up to 24 participants.
Betahistine dihydrochloride, the Otifex Therapeutics study drug, is an experimental drug being investigated for its potential as a treatment for middle ear disorders.
Betahistine dihydrochloride taken orally (via the mouth) has been approved for marketing by the Therapeutics Goods Administration (TGA) in Australia for the treatment of vertigo (dizziness) related to Meniere's syndrome (inner ear disorder).
Healthy participants have previously been dosed intranasally with the study drug in a separate study. In the first group of 8 participants (6 receiving the study drug and 2 receiving a placebo), the study drug was well tolerated intranasally with no clinical signs of any concern. There were two events reported that were related to an effect on the hearing in participants who received the active study drug. A review of the data by an independent audiologist concluded that both participants had pre-existing hearing defects prior to the study. That is why in this study, your ears will be examined prior to study entry, as part of determining your suitability to take part in the study.
In subsequent study groups, a further 32 participants (4 groups of 8 participants - 6 receiving the study drug and 2 receiving a placebo) have been dosed at the dose levels of 5, 10, 20 and 40 mg. All dose levels were very well tolerated and there were no significant changes in the hearing assessments noted.

This study is being conducted at the The Wesley Research Institute Clinical Trials Centre in conjunction with the Wesley Centre for Hyperbaric Medicine. This study is being sponsored by Otifex Therapeutics Pty Ltd (AUS).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 54126 0
Dr Dr Graeme Kay B.Biomed Sci (Hons.), MBBS, FRACGP
Address 54126 0
Wesley Centre for Hyperbaric Medicine
Ground Floor Suite 53
Sandford Jackson Building
30 Chasely Street
Auchenflower, QLD 4066
Country 54126 0
Australia
Phone 54126 0
+61 7 33716033
Fax 54126 0
+61 7 33711566
Email 54126 0
graeme@wesleyhyperbaric.com.au
Contact person for public queries
Name 54127 0
Ms Tracy Grierson
Address 54127 0
PO Box 499 Toowong Q 4066
Level MB2 The Wesley Hospital 451 Coronation Drive Auchenflower QLD 4066
Country 54127 0
Australia
Phone 54127 0
+61 7 3721 1541
Fax 54127 0
+61 7 3721 1594
Email 54127 0
TGrierson@wesleyresearch.com.au
Contact person for scientific queries
Name 54128 0
Dr Chris Wraight
Address 54128 0
Otifex Therapeutics Pty Ltd
Level 9, 278 Collins Street
Melbourne
VIC 3000
Country 54128 0
Australia
Phone 54128 0
+61 3 9657 0700
Fax 54128 0
+61 3 9657 0777
Email 54128 0
cwraight@otifex.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary