Clinical Trial Results:
A 6-month, prospective, randomized, multicenter, placebo-controlled safety study of OTO-104 given at 3-month intervals by intratympanic injection in subjects with unilateral Meniere's disease, followed by a 6-month open-label extension
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Summary
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EudraCT number |
2014-001337-86 |
Trial protocol |
GB |
Global end of trial date |
19 May 2016
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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 |
104-201403
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02265393 | ||
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, CA 92121
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Public contact |
Otonomy Medical Information, Otonomy Inc., medinfo@otonomy.com
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Scientific contact |
Otonomy Medical Information, 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 |
21 Dec 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
19 May 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
19 May 2016
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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 |
The objective of the first part of the study was to evaluate the safety of 2 intratympanic doses of 12 mg OTO-104, compared with placebo, given at 3-month intervals in subjects with unilateral Meniere’s disease.
The objective of the second part of the study was to continue to assess the safety of 2 intratympanic injections of 12 mg OTO-104 at 3 month intervals in an open-label phase.
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Protection of trial subjects |
Subjects in this study were to receive up to 4 intratympanic injections spaced 3 months apart. Prior to each injection, a numbing cream (containing lidocaine and prilocaine) was applied to the subject's tympanic membrane to manage pain/discomfort associated with the injection.
One of the primary concerns identified prior to the study was the potential for tympanic membrane perforation because of the injection procedure itself as well as any other risks associated with the study. To that end, a data safety monitoring board was organized, had their first meeting prior to the 1st subject's 3rd injection and then quarterly thereafter to review the study progress and the evolving safety data. The DSMB could be convened as needed, which it was when there was a serious adverse event that occurred during a subject's second injection. At each meeting, the DSMB was charged with evaluating safety data to determine whether the study should continue and concluded each time that the study could continue.
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Background therapy |
Subjects maintained their current standard-of-care treatment for Meniere’s disease while on study, including but not limited to, low-salt diet, diuretic, and/or betahistine. | ||
Evidence for comparator |
This was a safety study so there was no comparator. | ||
Actual start date of recruitment |
01 Jul 2014
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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 |
United Kingdom: 128
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Worldwide total number of subjects |
128
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EEA total number of subjects |
128
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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) |
106
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From 65 to 84 years |
22
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85 years and over |
0
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Recruitment
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Recruitment details |
Sixteen centers in the United Kingdom screened 144 subjects, with 128 randomized (103 to OTO-104; 25 subjects to placebo). In the second phase of the study all subjects received OTO-104 (n = 123; there were 5 discontinuations prior to the beginning of the second phase [Month 6]. | ||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects enrolled in the study were required to have unilateral Meniere’s disease as outlined by the American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) Committee on Hearing and Equilibrium in 1995 (Committee on Hearing and Equilibrium, 1995). A total of 144 subjects were screened to enroll 128 subjects. | ||||||||||||||||||||||||
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Period 1
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Period 1 title |
overall study (overall period)
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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, Carer, Assessor | ||||||||||||||||||||||||
Blinding implementation details |
Study site personnel, who were blinded to treatment assignment, provided the information (unique number) contained in the central randomization system notification to the unblinded qualified medical professional (QMP) responsible for preparing the syringe containing study drug. The QMP prepared the syringe from the contents of the study drug. The QMP prepared the syringe from the contents of the study drug package corresponding to the randomization system unique number.
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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 |
OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection) | ||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||
Investigational medicinal product name |
Dexamethasone suspension in a poloxamer 407 solution
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Investigational medicinal product code |
OTO-104
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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 |
The OTO-104 final product suspension for dosing was prepared by an unblinded qualified medical professional from 2 separate components, OTO-104 Diluent (1 vial) and OTO-104 Active (1 vial). An appropriate volume of OTO-104 Diluent was withdrawn and delivered into the OTO-104 Active vial to achieve a visually homogeneous suspension with a target drug concentration of 60 mg/mL. The subject is placed in a recumbent position with the treated ear upwards. The tympanic membrane is anesthetized by either covering the external surface of the posterior-inferior quadrant with topical lidocaine/prilocaine cream ([EMLA] cream) until the tympanic membrane is numb. The needle is inserted through the tympanic membrane with the bevel facing in an inferoposterior direction to a depth of approximately 2-3 mm just inferior to the round window niche, and with firm but gentle pressure, 0.2 mL is injected.
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Arm title
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Placebo | ||||||||||||||||||||||||
Arm description |
Poloxamer 407 solution | ||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||
Investigational medicinal product name |
Poloxamer 407
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Investigational medicinal product code |
P407
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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 |
Placebo (P407; OTO-104 Diluent) 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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Baseline characteristics reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Poloxamer 407 solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
All subjects who received at least one IT dose
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End points reporting groups
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Reporting group title |
OTO-104
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Reporting group description |
OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection) | ||
Reporting group title |
Placebo
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Reporting group description |
Poloxamer 407 solution | ||
Subject analysis set title |
Safety
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
All subjects who received at least one IT dose
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End point title |
Audiometry - Shift in Pure Tone Average [1] | ||||||||||||
End point description |
Change from Baseline in Pure Tone Average (PTA) calculated as the mean of air conduction thresholds at 500, 1000, and 2000 Hz.
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End point type |
Primary
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End point timeframe |
Up to 1 year
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics. |
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| Notes [2] - Subjects with PTA measurements at Baseline and Month 12 [3] - Subjects with PTA measurements at Baseline and Month 12 |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Meniere's Symptom Questionnaire [4] | ||||||||||||||||||||||||
End point description |
Change in Meniere's disease Questionnaire values; each category can be scored from 1 = none to 5 = extremely severe; a negative change = improvement.
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End point type |
Primary
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End point timeframe |
Up to 1 Year
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| Notes [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics. |
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| Notes [5] - Subjects with a questionnaire at Month 12 [6] - Subjects with a questionnaire at Month 12 |
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| No statistical analyses for this end point | |||||||||||||||||||||||||
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End point title |
Tympanic Membrane Perforation [7] | ||||||||||||||||||
End point description |
Perforations were rated as "Present" or "Not Present"; if a subject did not receive an otoscopy, then the perforation is listed as "Missing".
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End point type |
Primary
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End point timeframe |
Up to 12 months; otoscopy examinations were performed at 3, 6, 9, 12 months in the ear that received the injection(s) at Baseline, Month 3, Month 6, and Month 9, respectively.
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| Notes [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics. |
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| Notes [8] - OTO-104 subjects who had an Otoscopy at Baseline and last visit (up to Month 12). [9] - Placebo subjects who had an Otoscopy at Baseline and last visit (up to Month 12). |
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Tympanometry - Shift from Type A at Baseline | ||||||||||||||||
End point description |
Tympanometry assessments are used to assess the mobility and compliance of the tympanic membrane, pressure and volume in the middle ear, and function of the tympanic membrane, ossicles and eustachian tube. Type A is considered normal and the results presented here are for the percentage of treated ears that change from normal (Type A) at Baseline to another category.
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End point type |
Secondary
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End point timeframe |
Up to 1 Year
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| Notes [10] - Subjects randomized to OTO-104 with a tympanometry at Baseline and one at Month 6 after 2 injections [11] - Subjects randomized to Placebo with a tympanometry at Baseline and one at Month 9 after 2 injections [12] - Subjects with a tympanometry at Baseline and one at Month 12 after 4 injections |
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| No statistical analyses for this end point | |||||||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
Adverse events recorded at 6 months
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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 |
19.0
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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 a poloxamer 407 solution for intratympanic injection | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Poloxamer 407 solution | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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03 Jun 2014 |
Corrected the Visit Number for the Meniere’s symptom questionnaire from Visit 1 to Visit 2 (Synopsis, Page 11).
Modified the unblinding procedure to clarify that the physician administering the study drug is unblinded at the time of injection as well as accessing the study drug preparation records if the physician administering the study drug is not available or does not recollect the treatment administered (Section 5.3, Blinding, Page 19).
Replace “violation” with “deviation” (Section 7.1, Proscribed Therapy During the Study Period, pg. 20; Section 7.2, Symptomatic Relief Medications, pg. 20; Section 11.4, Subject Demographics, Baseline Disease Status, and Disposition, pg. 30
Modified the number and description of the responses to the Meniere’s Symptom Questionnaire (Section 8.2.6, Meniere’s Symptom Questionnaire, pg. 24).
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02 Oct 2015 |
Updated Medical Monitor contact to include Otonomy Drug Safety contact (Section 9.3, Contacting Sponsor Regarding Safety, page 28)
Included the following additional text in bold per DSMB recommendation after SAE:
“Using the tuberculin syringe pre-loaded with OTO-104 or placebo and equipped with a 26 gauge or 25 gauge needle, insert the needle through the tympanic membrane with the bevel facing in an inferoposterior direction to a depth of approximately 2-3 mm just inferior to the round window niche, and with firm but gentle pressure, inject 0.2 mL, taking care not to insert the needle further than necessary (Section 6.1, Study Drug Administration, page 19)
Time and Events Table/Study Flow Chart to include the C-SSRS assessment for Visits 4-6 and included a footnote (Table 1, pg. 13-14) .
Included the C-SSRS guidance (Section 8.2.7 C-SSRS Assessment, pg. 26)
Section changed for Safety stopping rules with the addition of C-SSRS (Changed from Section 8.2.7 to 8.2.8, page 26)
Included C-SSRS in the Safety Evaluation section (Section 11.7, page 35)Included C-SSRS guidance (Sections 11.7.6, 11.7.6.1, 11.7.6.2)
DSMB section referenced the incorrect section for the safety stopping rules:
"Should any untoward safety issue be observed, or any of the stopping rules outlined in Section 8.2.8 be invoked, the DSMB will schedule an immediate meeting to review the relevant safety data" (Section 8.2.8, page 40).
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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 | |||
