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
Otifex Therapeutics
24 participants
Apr 22, 2015
Interventional
Conditions
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).
Eligibility
Inclusion Criteria13
- Male or female volunteers aged 18 years or older.
- 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.
- Body mass index between 18 and 30 kg/m2 (inclusive).
- Healthy as assessed by medical history and physical examination.
- 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.
- 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.
- 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.
- Capable of providing written informed consent.
- Able to comply with study procedures and follow instructions from staff.
Exclusion Criteria26
- 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”.
- History of spontaneous pneumothorax, known lung bullae disease or known extensive lung scarring (risk of pulmonary barotrauma)
- Any history or presence of recurrent OME (including childhood history), myringotomy tubes (“grommets”), sinusitis, or known deviated nasal septum.
- Presence of excessive cerumen (ear wax).
- Positive pre-study test for alcohol or cotinine.
- 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.
- Participant has received an investigational drug within 30 days or 5 half-lives (whichever is longer) prior to the first dose of study drug.
- History of recurrent ENT infections, irritation or localised reaction to intranasally applied agents.
- Recent history of liver disease, or known hepatic or biliary abnormalities with the exception of Gilbert’s syndrome or asymptomatic gallstones.
- Females who are pregnant or breast-feeding.
- Recent ENT surgery (within 3 months of screening).
- History of bronchial asthma, gastric ulcers, or phaeochromocytoma.
- History of migraines.
- 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.
- 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.
- A history of tobacco use in the last 3 months.
- Current or history of symptomatic hypotension.
- Any clinically significant deviation from normal in physical examination, vital signs or Electrocardiogram (ECG) beyond what is consistent with normal, healthy population.
- 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
- A history of known hearing defects or tinnitus.
- A participant who for whatever reason, in the opinion of the investigator, should not participate in the study.
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Interventions
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.
Locations(1)
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ACTRN12615000657527