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 Meniere’s disease.
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Summary
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EudraCT number |
2018-001464-35 |
Trial protocol |
GB ES BE IT |
Global end of trial date |
22 Dec 2020
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Results information
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Results version number |
v1(current) |
This version publication date |
15 Dec 2022
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First version publication date |
15 Dec 2022
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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 |
104-201811
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT03664674 | ||
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, Otonomy, Inc., 1 6193232200,
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Scientific contact |
Medical Information, Otonomy, Inc., 1 844-686-4636, 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 |
25 Feb 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
22 Dec 2020
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Global end of trial reached? |
Yes
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Global end of trial date |
22 Dec 2020
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Was the trial ended prematurely? |
No
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General information about the trial
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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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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 used a placebo control, which the sponsor believed was the most direct way to measure the effect of the investigational product. In addition, the following points support use of a placebo control: • There is no drug product injected in the ear that is approved for the treatment of Ménière's disease. While ear injections of steroid solutions are used in clinical practice, there is need for research to find out if they work. • Betahistine has been approved by certain health authorities and is commonly used to treat Ménière's disease. It may have been an active control to compare its effect versus OTO-104 however, a review of previous trials conducted with betahistine concluded that there is “insufficient evidence to say whether betahistine has any effect on Ménière's disease.” In addition, a more recent trial 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 were recommended to continue taking medications they were taking before the study started. This could have included betahistine, diuretics (water pills), and/or a low salt diet (in other words, their standard of care). • The option of a sham injection of air or the patient not receiving any injection as a control was also considered. However, there was concern that this could accidentally “unblind” the patient (the patient would know they did not receive anything) if they could not tell if there was material in their ear. This could make it difficult to properly evaluate their vertigo, which could affect the study results. | ||
Actual start date of recruitment |
01 Oct 2018
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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: 60
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Country: Number of subjects enrolled |
Spain: 4
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Country: Number of subjects enrolled |
United Kingdom: 16
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Country: Number of subjects enrolled |
Belgium: 9
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Country: Number of subjects enrolled |
Germany: 15
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Country: Number of subjects enrolled |
Italy: 12
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Country: Number of subjects enrolled |
United States: 21
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Country: Number of subjects enrolled |
Turkey: 11
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Worldwide total number of subjects |
148
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EEA total number of subjects |
100
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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) |
108
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From 65 to 84 years |
40
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85 years and over |
0
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Recruitment
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Recruitment details |
Overall, 66 investigators were approved in Belgium, Germany, Italy, Poland, Spain, Turkey, United States, and United Kingdom) to conduct this study. Forty-two investigators enrolled subjects. First subject was randomized 14 December 2018; Last subject was randomized 29 September 2020. | |||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 317 subjects registered for this study and signed informed consent. Of these, 149 subjects were randomized and 148 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, Data analyst, 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 |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
OTO-104
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Investigational medicinal product code |
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Other name |
Dexamethasone
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Pharmaceutical forms |
Powder and solution for suspension for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
OTO-104 12 mg was administered as a single, 0.2 mL intratympanic injection of 60 mg/mL OTO-104. The OTO-104 final product suspension for dosing was prepared from 2 separate components: 16% poloxamer 407 solution (1 vial needed) and OTO-104 Active (1 vial needed). An appropriate volume of 16% poloxamer solution was withdrawn and delivered into the OTO 104 Active vial to achieve a visually homogeneous suspension of a target drug concentration of 60 mg/mL.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
The placebo was an aqueous solution of poloxamer 407. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
Poloxamer 407 solution
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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 |
Placebo was administered as a single, 0.2 mL intratympanic injection.
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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 (Week 12)
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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, Data analyst, Assessor | |||||||||||||||||||||
Blinding implementation details |
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 the injection. As the injection was give at the Baseline visit, no further IMP was 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 |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
OTO-104
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Investigational medicinal product code |
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Other name |
Dexamethasone
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Pharmaceutical forms |
Powder and solution for suspension for injection
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Routes of administration |
Intratympanic use
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Dosage and administration details |
OTO-104 12 mg was administered as a single, 0.2 mL intratympanic injection of 60 mg/mL OTO-104. The OTO-104 final product suspension for dosing was prepared from 2 separate components: 16% poloxamer 407 solution (1 vial needed) and OTO-104 Active (1 vial needed). An appropriate volume of 16% poloxamer solution was withdrawn and delivered into the OTO 104 Active vial to achieve a visually homogeneous suspension of a target drug concentration of 60 mg/mL.
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Arm title
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Placebo | |||||||||||||||||||||
Arm description |
The placebo was an aqueous solution of poloxamer 407. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
Poloxamer 407 solution
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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 |
Placebo was administered as a single, 0.2 mL intratympanic injection.
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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 |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
The placebo was an aqueous solution of poloxamer 407. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Intent to Treat Analysis Set
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The intent to treat analysis set included all randomized subjects all who receive study drug. Subjects were included in the treatment group to which
they were randomized regardless of the actual study drug received.
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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 |
The safety population included all subjects who received study drug. Note: The safety analysis set populations were displayed by the treatment the subject received.
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End points reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | ||
Reporting group title |
Placebo
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Reporting group description |
The placebo was an aqueous solution of poloxamer 407. | ||
Reporting group title |
OTO-104
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Reporting group description |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | ||
Reporting group title |
Placebo
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Reporting group description |
The placebo was an aqueous solution of poloxamer 407. | ||
Subject analysis set title |
Intent to Treat Analysis Set
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The intent to treat analysis set included all randomized subjects all who receive study drug. Subjects were included in the treatment group to which
they were randomized regardless of the actual study drug received.
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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 |
The safety population included all subjects who received study drug. Note: The safety analysis set populations were displayed by the treatment the subject received.
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End point title |
28-Day Average DVD at Week 12 (month 3) | ||||||||||||
End point description |
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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 |
Analysis of DVD Count at Week 12 | ||||||||||||
Statistical analysis description |
The count of definitive vertigo days for Week 12 was determined during the 4-week period between Weeks 9 and 12. A definitive vertigo day was any day the subject recorded a vertigo episode lasting at least 20 minutes and corresponding to a Vertigo Severity Score of 2 or more. Negative binomial model including coefficients for randomized treatment, sex, and lead-in period definitive vertigo days standardized to 28 days as a covariate.
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Comparison groups |
OTO-104 v Placebo
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Number of subjects included in analysis |
148
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Analysis specification |
Pre-specified
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Analysis type |
superiority [1] | ||||||||||||
P-value |
= 0.312 [2] | ||||||||||||
Method |
Generalized Linear Model – Neg Binomial | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-0.221
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.648 | ||||||||||||
upper limit |
0.207 | ||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.218
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| Notes [1] - Generalized Linear Model – Negative Binomial Regression Model with count data by subject transformed using the log-link function. [2] - The parameter estimate and confidence interval results back-transform to the ratio of adjusted mean definitive vertigo days (OTO-104/Placebo) to be 0.802 (0.523, 1.230). |
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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 |
23.0
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Reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
The placebo was an aqueous solution of poloxamer 407. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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16 Aug 2019 |
Version 2.0 implemented the following substantive changes:
• Clarified that subjects should continue to record their daily vertigo experience until Day 84 even if Visit 5 was performed early (out of window)
• Increased the number of study sites from approximately 50 to 60
• Increased upper age limit from 75 to 85
• Clarified that unblinding could be done through the study randomization system
• Clarified the topical lidocaine included lidocaine spray and that other related anesthetics may have been used
• Clarified that tympanometry did not need to be performed if the examiner decided that there was a contraindication to performing the procedure, such as tympanic perforation
• Corrected the protocol to indicate that at Screening audiograms should also have been conducted at 250 and 3000 Hz
• Clarified that medical staff who perform the otoscopic examinations did not need to be physicians, but should have been medical personnel who were experienced in performing otoscopic examinations
• Removed the Completer analysis set to be consistent with the draft statistical analysis plan |
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30 Jul 2020 |
Version 3.0 implemented the following substantive changes:
• Updated number of enrolled subjects from 160 to approximately 142 subjects
• Revised sample size calculation based on Negative Binomial model at Week 12 (replacing the generalized Poisson model)
• Analysis sets definitions revised and reflected primary analysis at Week 12 (the 4-week [28 day] interval from Week 9 to Week 12) and clarified when the ITT analysis set would be used.
• For subgroup analyses, added age categories at the higher end
• For subgroup analyses, added betahistine use as a subgroup
• Updated the primary efficacy endpoint to the 28-day average DVD at Week 12 (rather than number of DVD at Week 12)
• Added 2 new secondary endpoints (75% and 50% reduction from baseline in DVD) and refined the definition of previously named secondary endpoints
• Added 1 new exploratory endpoint and refined the definition of previously named secondary endpoints
• Described gate-keeping procedure to control the Type I error |
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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 | |||
