E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Meniere's disease is an inner ear disease. The symptoms are vertigo (room spinning), tinnitus (ringing in the ears or a feeling of fullness in the ears), and hearing loss. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10027183 |
E.1.2 | Term | Meniere's disease |
E.1.2 | System Organ Class | 10013993 - Ear and labyrinth disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To investigate the efficacy of OTO-104 in subjects with Meniere’s disease, as measured by the number of definitive vertigo days (DVD) at Week 12 (the 4-week interval from Week 9 through Week 12). |
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E.2.2 | Secondary objectives of the trial |
To investigate the safety profile of OTO-104 in subjects with Meniere’s disease. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Subject is a male or female aged 18 to 85 years, inclusive.
2. Subject has a diagnosis of definite unilateral Meniere's disease by 1995 AAO-HNS criteria.
3. Subject self-reports active, definitive vertigo episodes for the 2 months prior to the study lead-in period.
4. Subject has documented asymmetric sensorineural hearing loss at screening or within the past 12 months according to 1995 AAO-HNS criteria defined as one of the following:
a. The arithmetic mean of hearing thresholds (pure tone average, PTA) at 250, 500 and 1000 Hz of 15 dB or more higher than the PTA of 1000, 2000, and 3000 Hz,
b. The arithmetic mean of PTA at 500, 1000, 2000 and 3000 Hz is 20 dB or more poorer in the ear in question than on the opposite side,
c. It is the judgment of the Investigator that the subject's hearing loss meets reasonable audiometric criteria for hearing loss characteristic of Meniere's disease, and if so, it must be justified and documented, and discussed with the medical monitor.
5. If taking medication for Meniere’s disease (e.g., diuretics, vestibular suppressants, betahistine, antidepressants, or anxiolytics), subject must be on stable doses of the medication for at least 2 weeks prior to Screening and agrees to remain on stable doses of the medication for the duration of the study.
6. Female subjects of childbearing potential [i.e., not surgically sterile and/or not postmenopausal (≥12 months since last menstrual period and 45 years of age or older)] must have a negative urine pregnancy test before randomization. Women of childbearing potential who are not abstinent from sex with male partners may be entered into the study if they are using and willing to continue to use highly effective or “double barrier”
contraceptive precautions for the duration of the study (e.g., oral contraceptives, contraceptive implant or injection, intrauterine device, “double barrier” methods including male condom with diaphragm, male condom with cervical cap, male condom with spermicide, or diaphragm and spermicide).
7. Subject is willing to comply with the protocol and attend all study visits.
8. Subject is able to use the telephone to complete their daily diary.
9. Subject is able to provide written informed consent, including agreement to privacy language compliant with country and/or local requirements, before the initiation of any study-related procedures.
At the completion of the first 28 days of the lead-in period:
10. Subject has experienced and recorded at least 4 and a maximum of 22 definitive vertigo days during the 4-week lead-in period.
11. Subject completed at least 22 of 28 diary entries during the 4-week lead-in period. |
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E.4 | Principal exclusion criteria |
1. Subject has an infection in the ear, sinuses, or upper respiratory system at the time of randomization.
2. Subject is pregnant or lactating.
3. Subject has a history of immunodeficiency disease.
4. Subject has active or recent (<1 month prior to screening) middle ear disease, including but not limited to: chronic otitis media, acute otitis media, middle ear effusions, middle ear atelectasis, or cholesteatoma.
5. Subject has an abnormality of the tympanic membrane in the affected ear that would increase the risk associated with intratympanic injection including but not limited to monomeric tympanic membrane.
6. Subject has a history of significant middle ear or inner ear surgery, or endolymphatic sac surgery in the affected ear.
7. Subject has a history of previous use of intratympanic gentamicin in the affected ear.
8. Subject has a history of tympanostomy tubes with evidence of perforation or lack of closure in the affected ear.
9. Subject has used systemic steroids within 1 month prior to entering the lead-in period.
10. Subject has a history of previous use of intratympanic steroids in the affected ear.
11. Subject has experienced an adverse reaction to dexamethasone
12. Subject has a history of vestibular migraine. International Classification of Headache Disorders III criteria for vestibular migraine includes a current or past history of migraine with or without aura, vestibular symptoms of moderate or severe intensity lasting between 5 minutes and 72 hours, and at least half of episodes are associated with at least 1 of the 4 following migrainous features: unilateral headache, pulsating quality, photophobia, and visual aura.
13. Subject has history of drop attacks.
14. Subject is not able to accurately identify and report episodes of vertigo.
15. Subject has any other clinically significant illness, medical condition, or medical history that, in the Investigator’s or the medical monitor’s opinion, would prohibit the subject from participating in the study at screening or at the time of randomization.
16. Subject has used an investigational drug or device in the 3 months prior to screening.
17. Subject has a history of serious substance abuse (e.g. cocaine, heroin) within the preceding 6 months prior to screening.
18. Subject has previously been randomized to a clinical study of OTO-104. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The number of definitive vertigo days (DVD) at Week 12 [the 4-week (28-day) interval from Week 9 through Week 12]. Note: A DVD is defined as a day where the subject recorded at least one vertigo episode lasting at least 20 minutes and corresponds to a Vertigo Severity Score of 2 or more. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints:
• Severity of vertigo episodes as measured by the mean Vertigo Score at Week 12 [the 4-week (28-day) interval from Week 9 through Week 12]
• The number of days Sick at home or Bedridden as a consequence of vertigo at Week 12 [the 4-week (28-day) interval from Week 9 through Week 12]
• The change from baseline in vertigo frequency (VF) at Week 12 [the 4-week (28-day) interval from Week 9 through Week 12], where vertigo frequency is defined as the proportion of days during the 4- week interval where a definitive vertigo episode was recorded divided by the number of non-missing diary entries for the relevant interval
• Average daily count of vertigo episodes at Week 12 [the 4-week (28-day) interval from Week 9 through Week 12]
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 4, Week 8, Week 12 as specified in the endpoint description. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Germany |
Italy |
Poland |
Spain |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |