Clinical Trial Results:
A Multicenter, Randomized, Double-Blind Clinical Trial to Assess the Efficacy and Safety of Ciprofloxacin 0.3% plus Fluocinolone Acetonide 0.025% Otic Solution Compared to Ciprofloxacin 0.3% Otic solution and to Fluocinolone Acetonide 0.025% Otic Solution in the Treatment of Acute Otitis Media with Tympanostomy Tubes (AOMT) in Pediatric Patients. Estudio multicéntrico, randomizado, doble ciego para evaluar la eficacia y seguridad de Ciprofloxacino 0,3% más Fluocinolona Acetónido 0,025% solución ótica en comparación con Ciprofloxacino 0,3% solución ótica y con Fluocinolona Acetónido 0,025% solución ótica en el tratamiento de Otitis Media Aguda con Tubos de Timpanostomía en Pacientes Pediatricos

Trial information Top of page
Trial identification
Sponsor protocol code	CIFLOTIII/10IA02
Additional study identifiers
ISRCTN number	-
US NCT number	NCT01395966
WHO universal trial number (UTN)	-
Sponsors
Sponsor organisation name	Laboratorios SALVAT, S.A.
Sponsor organisation address	Gall 30-36, Esplugues de Llobregat, Spain, 08950
Public contact	Medical Department, Laboratorios SALVAT, S.A, +34 933946400, clinicaltrials@salvatbiotech.com
Scientific contact	Medical Director, Laboratorios SALVAT, S.A, +34 933946470, ejimenezv@salvatbiotech.com
Paediatric regulatory details
Is trial part of an agreed paediatric investigation plan (PIP)	No
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?	No
Results analysis stage
Analysis stage	Final
Date of interim/final analysis	16 Feb 2015
Is this the analysis of the primary completion data?	No
Global end of trial reached?	Yes
Global end of trial date	23 Jun 2014
Was the trial ended prematurely?	No
General information about the trial
Main objective of the trial	To evaluate the efficacy and safety of topical Ciprofloxacin 0.3% plus Fluocinolone Acetonide 0.025% otic solution. The primary endpoint was to demonstrate therapeutic superiority of Ciprofloxacin plus Fluocinolone Acetonide relative to Ciprofloxacin alone and to Fluocinolone Acetonide alone for time to cessation of otorrhea in pediatric patients suffering from acute otitis media with tympanostomy tubes (AOMT).
Protection of trial subjects	Not applicable
Background therapy	-
Evidence for comparator	-
Actual start date of recruitment	15 Jul 2011
Long term follow-up planned	No
Independent data monitoring committee (IDMC) involvement?	No
Population of trial subjects
Number of subjects enrolled per country
Country: Number of subjects enrolled	Spain: 13
Country: Number of subjects enrolled	Sweden: 1
Country: Number of subjects enrolled	Czech Republic: 1
Country: Number of subjects enrolled	Denmark: 10
Country: Number of subjects enrolled	Finland: 1
Country: Number of subjects enrolled	South Africa: 62
Country: Number of subjects enrolled	United States: 243
Worldwide total number of subjects	331
EEA total number of subjects	26
Number of subjects enrolled per age group
In utero	0
Preterm newborn - gestational age < 37 wk	0
Newborns (0-27 days)	0
Infants and toddlers (28 days-23 months)	121
Children (2-11 years)	209
Adolescents (12-17 years)	1
Adults (18-64 years)	0
From 65 to 84 years	0
85 years and over	0

Trial information Top of page

Subject disposition Top of page
Recruitment
Recruitment details	The recruitment period was from July 2011 to June 2014 in Europe (Czech Republic, Denmark, Finland, Spain and Sweden), South Africa and USA
Pre-assignment
Screening details	Patients between 6 months and 12 years with AOMT. Patients had to suffer from otorrhea for 3 weeks or less. Otorrhea had to be moderate or severe and purulent.
Pre-assignment period milestones
Number of subjects started	331
Number of subjects completed	331
Period 1
Period 1 title	Study period (overall period)
Is this the baseline period?	Yes
Allocation method	Randomised - controlled
Blinding used	Double blind
Roles blinded	Subject, Investigator, Monitor, Data analyst, Carer, Assessor
Blinding implementation details	The patient was randomized using IWRS. All study medication products (test and comparators) had the same packaging and labels, and the boxes in which the study medication was packaged, shipped, and dispensed were identical in appearance. The central laboratory was blinded to the treatment assignment of the patient from whom the sample was collected.
Arms
Are arms mutually exclusive	Yes
Arm title	CIPRO + FLUO
Arm description	-
Arm type	Experimental
Investigational medicinal product name	Ciprofloxacin plus Fluocinolone acetonide
Investigational medicinal product code
Other name
Pharmaceutical forms	Ear drops, solution in single-dose container
Routes of administration	Auricular use
Dosage and administration details	Administer the contents of one 0.25ml single dose vial twice a day to the affected ear(s) for seven days
Arm title	CIPRO
Arm description	-
Arm type	Active comparator
Investigational medicinal product name	Ciprofloxacin
Investigational medicinal product code
Other name
Pharmaceutical forms	Ear drops, solution in single-dose container
Routes of administration	Auricular use
Dosage and administration details	Administer the contents of one 0.25ml single dose vial twice a day to the affected ear(s) for seven days
Arm title	FLUO
Arm description	-
Arm type	Active comparator
Investigational medicinal product name	Fluocinolone acetonide
Investigational medicinal product code
Other name
Pharmaceutical forms	Ear drops, solution in single-dose container
Routes of administration	Auricular use
Dosage and administration details	Administer the contents of one 0.25ml single dose vial twice a day to the affected ear(s) for seven days
Number of subjects in period 1 CIPRO + FLUO CIPRO FLUO Started 112 109 110 Completed 104 99 91 Not completed 8 10 19      Consent withdrawn by subject 1 1 3      Physician decision - - 2      Adverse event, non-fatal 3 3 4      early temination - - 1      Lost to follow-up 2 1 1      Tube absent 1 - -      Lack of efficacy 1 4 7      Protocol deviation - 1 1

Subject disposition Top of page

Baseline characteristics Top of page
Baseline characteristics reporting groups
Reporting group title	CIPRO + FLUO
Reporting group description	-
Reporting group title	CIPRO
Reporting group description	-
Reporting group title	FLUO
Reporting group description	-
Reporting group values CIPRO + FLUO CIPRO FLUO Total Number of subjects 112 109 110 331 Age categorical Units: Subjects     6 months to 12 years 112 109 110 331 Gender categorical Units: Subjects     Female 48 43 42 133     Male 64 66 68 198

Baseline characteristics Top of page

End points Top of page
End points reporting groups
Reporting group title	CIPRO + FLUO
Reporting group description	-
Reporting group title	CIPRO
Reporting group description	-
Reporting group title	FLUO
Reporting group description	-

End points Top of page

Primary: Time to cessation of otorrhea Top of page
End point title	Time to cessation of otorrhea
End point description
End point type	Primary
End point timeframe	During all study (22 days)
End point values CIPRO + FLUO CIPRO FLUO Number of subjects analysed 112 109 110 Units: day     median (confidence interval 95%) 3.75 (3.04 to 4.39) 7.69 (4.78 to 11.44) 22 (7.43 to 22)
Statistical analysis title	Time to cessation of otorrhea
Statistical analysis description	The time to cessation of otorrhea was calculated in days. Survival analysis was done using non-parametric Kaplan-Meier method. Patients who did not discontinue prematurely and for whom the otorrhea still persists at the end of the study (or Day 22 if earlier) are censored at Day 22. Patients who discontinued for any reason or took rescue medication are censored at Day 22.
Comparison groups	CIPRO + FLUO v CIPRO v FLUO
Number of subjects included in analysis	331
Analysis specification	Pre-specified
Analysis type	superiority
P-value	< 0.05
Method	Logrank
Confidence interval

Primary: Time to cessation of otorrhea Top of page

Adverse events Top of page
Adverse events information
Timeframe for reporting adverse events	All the study
Assessment type	Non-systematic
Dictionary used for adverse event reporting
Dictionary name	MedDRA
Dictionary version	13.0
Reporting groups
Reporting group title	CIPRO+FLUO
Reporting group description	-
Reporting group title	CIPRO
Reporting group description	-
Reporting group title	FLUO
Reporting group description	-
Serious adverse events CIPRO+FLUO CIPRO FLUO Total subjects affected by serious adverse events      subjects affected / exposed 0 / 113 (0.00%) 0 / 108 (0.00%) 0 / 106 (0.00%)      number of deaths (all causes) 0 0 0      number of deaths resulting from adverse events 0 0 0
Frequency threshold for reporting non-serious adverse events: 0%
Non-serious adverse events CIPRO+FLUO CIPRO FLUO Total subjects affected by non serious adverse events      subjects affected / exposed 7 / 113 (6.19%) 4 / 108 (3.70%) 9 / 106 (8.49%) Ear and labyrinth disorders Auricular swelling      subjects affected / exposed 1 / 113 (0.88%) 0 / 108 (0.00%) 0 / 106 (0.00%)      occurrences all number 1 0 0 Ear pain      subjects affected / exposed 1 / 113 (0.88%) 1 / 108 (0.93%) 2 / 106 (1.89%)      occurrences all number 1 1 2 Otorrhoea      subjects affected / exposed 1 / 113 (0.88%) 0 / 108 (0.00%) 0 / 106 (0.00%)      occurrences all number 1 0 0 Ear canal erythema      subjects affected / exposed 0 / 113 (0.00%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 0 0 1 Ear discomfort      subjects affected / exposed 0 / 113 (0.00%) 1 / 108 (0.93%) 0 / 106 (0.00%)      occurrences all number 0 1 0 Ear haemorrhage      subjects affected / exposed 0 / 113 (0.00%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 0 0 1 Skin and subcutaneous tissue disorders Excessive granulation tissue      subjects affected / exposed 1 / 113 (0.88%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 1 0 1 Rash      subjects affected / exposed 1 / 113 (0.88%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 1 0 1 Dermatitis      subjects affected / exposed 0 / 113 (0.00%) 1 / 108 (0.93%) 0 / 106 (0.00%)      occurrences all number 0 1 0 Eczema      subjects affected / exposed 0 / 113 (0.00%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 0 0 1 Infections and infestations Otitis media      subjects affected / exposed 2 / 113 (1.77%) 1 / 108 (0.93%) 3 / 106 (2.83%)      occurrences all number 2 1 3 Otitis media acute      subjects affected / exposed 1 / 113 (0.88%) 1 / 108 (0.93%) 0 / 106 (0.00%)      occurrences all number 1 1 0 Ear infection fungal      subjects affected / exposed 0 / 113 (0.00%) 0 / 108 (0.00%) 1 / 106 (0.94%)      occurrences all number 0 0 1 Otitis externa      subjects affected / exposed 0 / 113 (0.00%) 1 / 108 (0.93%) 0 / 106 (0.00%)      occurrences all number 0 1 0

Adverse events Top of page

More information Top of page
Substantial protocol amendments (globally)
Were there any global substantial amendments to the protocol? Yes
Date	Amendment
02 Mar 2012	• Revised the medical monitor for Canada and the United States and added contact information for medical monitors • Increased the number of study sites and add new countries
20 Jun 2012	Added a new country to the list of countries for planned study sites Updated procedure for return of study medication
16 May 2013	Changed sponsor contact Added and revised the medical monitors in all countries
Interruptions (globally)
Were there any global interruptions to the trial? No
Limitations and caveats
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
None reported

More information Top of page