Clinical Trial Results:
Effectiveness of Transtympanic Steroids in unilateral Ménière's disease: a Randomised Controlled Double-Blind Trial
Summary
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EudraCT number |
2008-004803-78 |
Trial protocol |
GB |
Global end of trial date |
04 May 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
14 May 2016
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First version publication date |
14 May 2016
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Other versions |
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Summary report(s) |
End of Trial Summary Report |
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 |
1.1
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Imperial College London
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Sponsor organisation address |
South Kensington, London, United Kingdom,
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Public contact |
Dr Mitesh Patel, Imperial College London, 0044 208 223 7241, Mitesh.Patel1@imperial.ac.uk
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Scientific contact |
Dr Mitesh Patel
Professor Adolfo Bronstein, Imperial College London, 0044 208 223 7241, Mitesh.Patel1@imperial.ac.uk
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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 |
04 May 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
04 May 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
04 May 2015
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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 |
There are 20-24% of patients with Meniere's disease who do not respond to first line treatment with diet modification and oral drugs. One of the well established alternative treatment option is the minimally invasive transtympanic treatment, where drugs are injected locally through the ear drum. The most commonly used drug for injection is Gentamicin. Gentamicin provides effective control of vertigo by toxic action on the labyrinth. But it is potentially harmful to hearing organ also and may produce further hearing deterioration in 25% of patients and profound loss in 7%. Recently, steroids are used as an alternative by many ENT surgeons with reports that it provides relief of vertigo without hearing loss or maybe hearing improvemnet also. However, this has not been proven. The main research question is to compare the two drugs and establish their role in Meniere's patients who are not responding to medical treatment.
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Protection of trial subjects |
An audiogram was obtained before the second injection (2 weeks after the first) which was assessed by a blinded consultant (MH) and reported to the pharmacy. Following a 20dB (decibel) drop in hearing across any two consecutive frequencies, the pharmacy (without informing the trial team) switched gentamicin for saline (Figure 1). As steroids do not disturb hearing, patients randomised to steroid were given a second steroid injection.
Non responders: If vertigo attacks returned (=non-responder) an unblinded consultant (BMS) prescribed a further course of intratympanic injections but the patient and everybody else remained blind. The clinician had the choice to prescribe the same drug or swap, basing this decision on the patient’s response to previous injections.
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Background therapy |
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Evidence for comparator |
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Actual start date of recruitment |
02 Nov 2009
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Efficacy, Scientific research | ||
Long term follow-up duration |
2 Years | ||
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 |
United Kingdom: 60
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Worldwide total number of subjects |
60
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EEA total number of subjects |
60
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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) |
50
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From 65 to 84 years |
10
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85 years and over |
0
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Recruitment
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Recruitment details |
Patients were recruited between November 2009-May 2013 | ||||||||||||||||||
Pre-assignment
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Screening details |
Inclusion criteria were patients 18-70 years of age with definite unilateral MD having experienced at least 2 episodes of rotational vertigo lasting at least 20min in the previous 6 months and shown no response to standard medical treatment. | ||||||||||||||||||
Pre-assignment period milestones
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Number of subjects started |
60 | ||||||||||||||||||
Number of subjects completed |
60 | ||||||||||||||||||
Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Investigator, Subject | ||||||||||||||||||
Blinding implementation details |
The double-blind randomisation sequence was generated by constructing 15 blocks of 4 possible combinations, containing 2 Steroid and 2 Gentamicin treatments, to keep drug allocation roughly equal throughout recruitment. The randomisation sequence was retained and concealed by the Charing Cross Hospital and Leicester Royal Infirmary pharmacy aseptic units
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Gentamicin (control) | ||||||||||||||||||
Arm description |
Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Methylprednisolone
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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 |
2 initial doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. Repeat injections if necessary over 2 years.
The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.
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Investigational medicinal product name |
Gentamicin
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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 |
2 initial doses (spaced 2 weeks apart) of 1ml of 40mg/ml. Repeat injections if necessary over 2 years.
The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.
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Arm title
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Methylprednisolone | ||||||||||||||||||
Arm description |
Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. | ||||||||||||||||||
Arm type |
Active comparator | ||||||||||||||||||
Investigational medicinal product name |
Methylprednisolone
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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 |
2 initial doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. Repeat injections if necessary over 2 years.
The patients lay supine on a couch with the head turned away from the treated ear. The ear canal was sprayed with 2 to 3 squirts of Lidocaine spray (Xylocaine spray™ 10mg/spray). After 60 seconds the ear canal was completely aspirated. The injection syringe was attached to a 22Gauge spinal needle which, under microscopic control, was inserted in the inferior aspect of the pars tensa. The injection continued until a fluid level could be seen to fill the tympanic cavity and the volume injected was recorded. The patient was asked not to swallow or speak for 20 minutes. Immediately after treatment, all 60 patients were issued the same (Cawthorne-Cooksey) rehabilitation exercises and instructed to begin performing them after 3 days, twice daily, beginning slowly and grading their intensity progressively over 4 weeks.
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Notes [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero. Justification: Two patient crossed over from methylprednisolone to gentamicin due to non-response One patient in the gentamicin arm was lost to follow-up. |
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Baseline characteristics reporting groups
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Reporting group title |
Gentamicin (control)
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Reporting group description |
Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Methylprednisolone
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Reporting group description |
Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Gentamicin (control)
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Reporting group description |
Gentamicin – administered intratympanically. Gentamicin is commonly used as an antibiotic but used for its vestibular suppressant action, i.e., reducing vestibular function and vertigo attacks. There is central compensation of reduced vestibular function following treatment. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 40mg/ml. | ||
Reporting group title |
Methylprednisolone
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Reporting group description |
Methylprednisolone – Administered intratympanically. Methylprednisolone is a synthetic cortico-steroid drug. It has predominant anti-inflammatory properties with some anti-allergic and mineralocorticoid effects. The treatment was 2 doses (spaced 2 weeks apart) of 1ml of 62.5mg/ml. |
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End point title |
Attacks of vertigo (Primary Outcome) | ||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
18-24 months follow-up as per AAO-HNS recommendations.
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Statistical analysis title |
Outcome measure stats | ||||||||||||
Statistical analysis description |
There was a significant reduction of vertigo attacks in the final six 6 months (time; F[1,58]65.0; P<0.001). Mean number of vertigo attacks fell from 19.9 to 2.5 in the gentamicin arm and from 16.4 to 1.6 in the steroid arm. There was no significant difference between drugs (drug; F[1,58]1.2;P=0·271, time x drug interaction; F[1,58]0.43; P=0.514).
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Comparison groups |
Gentamicin (control) v Methylprednisolone
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||
P-value |
= 0.514 [1] | ||||||||||||
Method |
ANOVA | ||||||||||||
Confidence interval |
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Notes [1] - No difference between drugs for primary outcome measure |
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End point title |
Change in Hearing threshold | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
2 years follow-up as per AAO-HNS recommendations
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Notes [2] - Intention-to-treat [3] - Intention-to-treat |
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Statistical analysis title |
Hearing Analysis (Secondary Outcome) | ||||||||||||
Comparison groups |
Gentamicin (control) v Methylprednisolone
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Number of subjects included in analysis |
60
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Analysis specification |
Pre-specified
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Analysis type |
equivalence [4] | ||||||||||||
P-value |
= 0.18 [5] | ||||||||||||
Method |
ANOVA | ||||||||||||
Confidence interval |
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Notes [4] - Hearing levels did not significantly change from baseline over the 24 months follow-up (time; F[6,54]2.13; P=0.065). There was no significant difference between drugs (drug F[1,58]0.03; P=0.964 ;time x drug interaction; F[6,54]1.55; P=0.18). [5] - No significant difference between arms |
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Adverse events information
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Timeframe for reporting adverse events |
2 years follow-up
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
SNOMED CT | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
RF2
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Reporting groups
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Reporting group title |
Adverse Events (Gentamicin)
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Reporting group description |
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Reporting group title |
Adverse Events (Methylprednisolone)
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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19 Dec 2009 |
Otoacoustic emission testing removed from audiological testing battery due to non-availability of equipment |
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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 |