Clinical trial NCT02630992: Reduced Clavulanate Formulation of Amoxicillin-Clavulanate in Children 6-23 Months With Acute Otitis Media
Official title: Reduced Clavulanate Formulation of Amoxicillin-Clavulanate in Children 6-23 Months With Acute Otitis Media
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Acute Otitis Media
Keywords: ear infections
antibiotics
antibiotic resistance
pediatrics
infants
children
amoxicillin-clavulanate
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
First posted: 2015-12-15
Enrollment: 112
Sex: ALL
Minimum age (years): 6
Maximum age (years): 23
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: To evaluate the safety profile of amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 90/3.2 mg/kg/day (formulation 1) or at 80/2.85 mg/kg/day (formulation 2) in two divided doses for 10 days. Investigators will focus on the proportion of subjects who develop protocol-defined diarrhea and proportion who develop diaper dermatitis that occasions the prescription of antifungal medication.

Detailed description: Amoxicillin-clavulanate potassium has been shown to be efficacious in eradicating causative pathogens in acute otitis media (AOM) with resulting high clinical cure rates at end-of-treatment (85%). However, relatively high rates (\~25%) of clinically significant diarrhea have been reported, the occurrence of which has been directly related to the clavulanate potassium component of the drug combination. A reduced concentration of clavulanate potassium in the drug formulation would be expected to have an improved safety profile regarding the occurrence of diarrhea. This study will examine whether the concentration of the clavulanate potassium component of amoxicillin-clavulanate potassium could be reduced in the treatment of children 6 months through 23 months of age diagnosed with AOM using stringent criteria. A total of 75 participants (n=75) with AOM will receive amoxicillin-clavulanate potassium (600 mg/21.5 mg/5 mL; 28:1) administered at 90/3.2 mg/kg/day (formulation 1) or at 80/2.85 mg/kg/day (formulation 2) in two divided doses for 10 days.

The primary outcome measure will be rates of clinically significant diarrhea and diaper dermatitis. These rates will be compared with the rate observed in our previous studies of AOM in children who received amoxicillin-clavulanate potassium (600 mg/42.9 mg/5 mL; 14:1) administered at 90/6.4 mg/kg/day in two divided doses for 10 days.

A subset of this group will have pharmacokinetic studies performed. Each participant that agrees will have a single blood draw (n=50). Investigators will analyze amoxicillin and clavulanate potassium in the blood samples using validated methods.

Eligibility criteria: Inclusion Criteria:

* Age range: 6 to 23 months
* Evidence of AOM
* Recent (within 48 hours) onset of signs and symptoms.
* Middle ear effusion evidenced by the presence of at least 2 of the following: decreased or absent mobility of the tympanic membrane (TM), yellow of white discoloration of the TM, and/or opacification of the TM
* Acute inflammation evidenced by one of the following: 1+ bulging of the TM with either intense erythema or otalgia or 2+ or 3+ bulging of the TM

Exclusion Criteria:

* Toxic appearance (capillary refill \>3 seconds, systolic blood pressure \<60 mm Hg)
* Inpatient hospitalization
* Clinical or anatomical characteristics that might obscure response to treatment (e.g., tympanostomy tubes in place, cleft palate, Down syndrome)
* Sensorineural hearing loss (unilateral or bilateral)
* Allergy to amoxicillin or amoxicillin clavulanate
* Recent treatment of AOM within the last 14 days

Primary outcomes:
measure: The Distribution of Participants Receiving Formulation 1 for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of amoxicillin-clavulanate until day 12.
measure: The Distribution of Participants Receiving Formulation 2 for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of amoxicillin-clavulanate until day 12.
measure: The Distribution of Participants Receiving Formulation 1 for Whom Diaper Dermatitis Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of amoxicillin-clavulanate until day 12.
measure: The Distribution of Participants Receiving Formulation 2 for Whom Diaper Dermatitis Was Reported and Associated With Study Product
timeFrame: Day 1 of administration of amoxicillin-clavulanate until day 12.
Secondary outcomes:
measure: The Distribution of Participants Receiving Formulation 1 Categorized as Treatment Failure (TF) at or Before the End-of-Treatment Visit
timeFrame: From 72 hours after the initial AOM until the end-of-treatment visit. The mean day for this visit was 14.9.
measure: The Distribution of Participants Receiving Formulation 2 Categorized as Treatment Failure (TF) at or Before the End-of-Treatment Visit
timeFrame: From 72 hours after the initial AOM until the end-of-treatment visit. The mean day for this visit was 13.9.
measure: The Distribution of Participants Receiving Formulation 1 Demonstrating Resolution of Acute Otitis Media (AOM) and Substantial Improvement of Symptoms That Would Allow Discontinuing Therapy at the Day 7 Visit
timeFrame: Day 1 of administration of amoxicillin-clavulanate until the day 7 visit. The mean day for this visit was 7.5.
measure: The Distribution of Participants Receiving Formulation 2 Demonstrating Resolution of Acute Otitis Media (AOM) and Substantial Improvement of Symptoms That Would Allow Discontinuing Therapy at the Day 7 Visit
timeFrame: Day 1 of administration of amoxicillin-clavulanate until the day 7 visit. The mean day for this visit was 7.6.
measure: The Mean Score Representing the Parent or Guardian's Level of Satisfaction With Therapy for Participants Receiving Formulation 1
timeFrame: The end-of-treatment visit. The mean day for this visit was 14.9.
measure: The Mean Score Representing the Parent or Guardian's Level of Satisfaction With Therapy for Participants Receiving Formulation 2
timeFrame: The end-of-treatment visit. The mean day for this visit was 13.9.
measure: Distribution of Population Plasma Concentration of Amoxicillin According to Time For Participants Receiving Formulation 1
timeFrame: From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after.
measure: Distribution of Population Plasma Concentration of Amoxicillin According to Time For Participants Receiving Formulation 2
timeFrame: From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after.
measure: Distribution of Population Plasma Concentration of Clavulanate According to Time For Participants Receiving Formulation 1
timeFrame: From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after.
measure: Distribution of Population Plasma Concentration of Clavulanate According to Time For Participants Receiving Formulation 2
timeFrame: From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after.
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh School of Medicine; Children's Hospital of Pittsburgh of UPMC
name: Nader Shaikh, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoberman A, Paradise JL, Rockette HE, Jeong JH, Kearney DH, Bhatnagar S, Shope TR, Muniz G, Martin JM, Kurs-Lasky M, Haralam M, Pope MA, Nagg JP, Zhao W, Miah MK, Beumer J, Venkataramanan R, Shaikh N. Reduced-Concentration Clavulanate for Young Children with Acute Otitis Media. Antimicrob Agents Chemother. 2017 Jun 27;61(7):e00238-17. doi: 10.1128/AAC.00238-17. Print 2017 Jul.