Clinical Trial Results:
A prospective, randomized, double blind, placebo-controlled, multicenter, Phase 3 efficacy and safety study of OTO-104 given as a single intratympanic injection in subjects with unilateral Ménière's disease.
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Summary
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EudraCT number |
2015-004496-71 |
Trial protocol |
GB BE DE IT |
Global end of trial date |
31 Aug 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
13 Dec 2021
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First version publication date |
13 Dec 2021
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
104-201508
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02717442 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Otonomy, Inc.
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Sponsor organisation address |
4796 Executive Drive, San Diego, United States, 92121
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Public contact |
Medical Information Center, Otonomy Inc., medinfo@otonomy.com
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Scientific contact |
Otonomy Medical Information Center, Otonomy Inc., medinfo@otonomy.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
29 Mar 2019
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
31 Aug 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Aug 2017
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
To confirm the efficacy of OTO-104 in subjects with Ménière'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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Protection of trial subjects |
The study was conducted in accordance with current Good Clinical Practice (GCP). This study was undertaken only after a designated Independent Ethics Committee (IEC) had fully approved the protocol and the sponsor had received a copy of the approval. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures according to local requirements after the nature of the study had been fully explained. Each subject was informed that they were free not to participate in the study and that they could withdraw consent to participate at any time. Subjects who chose to participate signed an informed consent document. Lastly, to decrease pain from the injection procedure, the tympanic membrane was anesthetized with a topical lidocaine/prilocaine cream.
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Background therapy |
Subjects were allowed to continue symptomatic relief medications for Ménière's disease symptoms, prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications they were on when they started in the trial. They were requested to maintain the same regimen throughout the study. | ||
Evidence for comparator |
The study contained a placebo control, which the sponsor believed is the most direct way to measure the effect of this investigational product. In addition, the following considerations would also lead to the conclusion that a placebo control is appropriate: • There is no drug product administered intratympanically that is approved for the treatment of Ménière's disease. While intratympanic steroid solutions are used in clinical practice, there is need for additional clinical research to support their effectiveness. In addition, the intratympanic administration of gentamicin acts through an ototoxic effect and its use is typically restricted in Ménière's disease patients with residual hearing. • Betahistine is approved and widely used for Ménière's disease, although a Cochrane Review concludes that there is “insufficient evidence to say whether betahistine has any effect on Ménière's disease”. In addition, a recent article in The BMJ concluded that in the “randomised, placebo-controlled study described, the effects of two different doses of betahistine could not be distinguished from a patient reported effect caused by placebo intervention.” Therefore, its value as an active control is unknown. • Notwithstanding, subjects are recommended to continue on medications they are on prior to the study start, which may include betahistine, diuretics, and/or a low salt diet (i.e., their standard of care). The requirement is simply that they must have the requisite number of definitive vertigo days in order to be randomized. • The option of a sham injection (i.e., air) was also considered. However, there was concern that this could inadvertently “unblind” the subject if there were no perception of material in the ear. | ||
Actual start date of recruitment |
21 Mar 2016
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Poland: 62
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Country: Number of subjects enrolled |
United Kingdom: 49
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Country: Number of subjects enrolled |
Belgium: 8
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Country: Number of subjects enrolled |
France: 9
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Country: Number of subjects enrolled |
Germany: 28
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Country: Number of subjects enrolled |
Italy: 18
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Worldwide total number of subjects |
174
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EEA total number of subjects |
174
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
144
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From 65 to 84 years |
30
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85 years and over |
0
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Recruitment
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Recruitment details |
Overall, 57 investigators were approved in Europe (Belgium, France, Germany, Italy, Poland, United Kingdom) were approved to conduct this study. Forty-nine investigators enrolled subjects. First subject was randomized 21 March 2016; Last subject was randomized 22 August 2017. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 360 subjects registered for this study and signed informed consent. Of these, 176 subjects were randomized and 174 subjects received study drug. The most common reason for screen failure was that there was not a sufficient number of definitive vertigo days in the 28-day lead-in period. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
Baseline
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind [1] | ||||||||||||||||||||||||
Roles blinded |
Subject, Monitor, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
A treatment syringe (OTO-104 or placebo) was pre-loaded by an unblinded person. Each syringe was prepared to prevent visualization of syringe contents by all other study staff through the use of a syringe overlabel. Any interaction with subjects with regard to the collection, review or discussion of study assessments, with the exception of otoscopic exams, was done by the study coordinator, audiologist or someone other than the person who prepared the syringe and the physician who administered
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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OTO-104 | ||||||||||||||||||||||||
Arm description |
0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
OTO-104
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
Subjects are administered the single intratympanic injection at baseline.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
0.2 mL poloxamer 407 aqueous solution | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
Subjects are administered a single intratympanic injection at baseline.
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| Notes [1] - The roles blinded appear to be inconsistent with a double blind trial. Justification: Since the OTO-104 and placebo looked different (OTO-104 is a white suspension and placebo is clear), the investigator who administered the injection was unblinded. However, the other staff remained blinded since care was taken in preparation of the dosing syringe and examination of the ear post-injection. A blinding plan was created for each site prior to the first dose administration. |
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Period 2
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Period 2 title |
Follow-up
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Is this the baseline period? |
No | ||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind [2] | ||||||||||||||||||||||||
Roles blinded |
Subject, Monitor, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
This period is comprised of all post-Baseline clinic visits. Because treatment was administered one time at the Baseline visit, the only blinding detail that is relevant is that only the unblinded staff member can perform the otoscopic examination. Any interaction with subjects with regard to the collection, review or discussion of study assessments, was done by someone other than the unblinded person who prepared the syringe and the investigator who administered the dose at the Baseline visit
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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OTO-104 | ||||||||||||||||||||||||
Arm description |
0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
OTO-104
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Suspension for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
There is no drug administered during the follow-up period. Subjects efficacy and safety are attributed to the single dose administered at baseline.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
0.2 mL poloxamer 407 aqueous solution | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for solution for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
There is no drug administered during the follow-up period. Subjects efficacy and safety are attributed to the single dose administered at baseline.
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| Notes [2] - The roles blinded appear to be inconsistent with a double blind trial. Justification: Since the OTO-104 and placebo looked different (OTO-104 is a white suspension and placebo is clear), the investigator who administered the injection was unblinded. However, the other staff remained blinded since care was taken in preparation of the dosing syringe and examination of the ear post-injection. A blinding plan was created for each site prior to the first dose administration. |
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Baseline characteristics reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
0.2 mL poloxamer 407 aqueous solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All randomized subjects that received study drug (OTO-104 or placebo)
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Subject analysis set title |
Full Analysis Set-1
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Subjects who were randomized, received study drug, had a baseline definitive vertigo measurement for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline, i.e., at least 1 post-baseline daily diary entry.
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End points reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution | ||
Reporting group title |
Placebo
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Reporting group description |
0.2 mL poloxamer 407 aqueous solution | ||
Reporting group title |
OTO-104
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Reporting group description |
0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution | ||
Reporting group title |
Placebo
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Reporting group description |
0.2 mL poloxamer 407 aqueous solution | ||
Subject analysis set title |
Safety Analysis Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All randomized subjects that received study drug (OTO-104 or placebo)
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Subject analysis set title |
Full Analysis Set-1
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
Subjects who were randomized, received study drug, had a baseline definitive vertigo measurement for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline, i.e., at least 1 post-baseline daily diary entry.
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End point title |
Definitive Vertigo Day | ||||||||||||
End point description |
A Definitive Vertigo Day (DVD) was defined as a day where the subject recorded at least 1 vertigo episode lasting at least 20 minutes corresponding to a Vertigo Severity Score of 2 or more. If multiple episodes occurred on a given day, subjects were instructed to record the Vertigo Severity Score for the worst episode experienced during the day.
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End point type |
Primary
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End point timeframe |
Month 3 - defined as the 4 week interval from Week 9 and Week 12.
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Statistical analysis title |
Generalized Poisson Linear Mixed Model | ||||||||||||
Statistical analysis description |
The model included fixed effects for randomized treatment group (OTO 104 vs placebo), sex (male vs female), study week (4, 8, 12), a treatment group by study week interaction, and the count of lead-in period DVD standardized to 28 days as a covariate. Study week was modeled as a categorical variable. The model also included a random intercept to account for the longitudinal design; an offset for the log of the number of daily diary entries recorded for each 4-week post-baseline period was added
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Comparison groups |
OTO-104 v Placebo
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Number of subjects included in analysis |
174
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.029 | ||||||||||||
Method |
Poisson | ||||||||||||
Confidence interval |
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| Notes [1] - The count of DVD at each 4-week study period standardized to 28 days was summarized using descriptive statistics. In addition, the count of DVD at each 4-week study period was summarized (not standardized to 28 days) descriptively. The ratio of the adjusted means from the model comparing OTO-104 to placebo at Week 12, the corresponding 95% CI, and p-value was presented. |
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events were recorded as observed or reported during or after dosing up to the final visit (Day 84).
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Assessment type |
Non-systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
0.2 mL of a 6% suspension of dexamethasone on poloxamer 407 aqueous solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
0.2 mL poloxamer 407 aqueous solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 2% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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15 Oct 2015 |
Added EudraCT Number and modified storage condition of the drug to be refrigerated as opposed to frozen. |
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13 Jan 2016 |
- Additional exclusion criteria to hypersensitivity to dexamethasone or any of the OTO-104 excipients.
- Modified Section 1.1, Study Rationale to include rationale for dose selection.
- Modified statement regarding contacting the medical monitor if an unblinding has occurred.
- Changed pharmacovigilance vendor, and therefore contacts were updated.
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
