Reduced Clavulanate Formulation of Amoxicillin-Clavulanate in Children 6-23 Months With Acute Otitis Media

Study Overview
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Brief Summary
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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
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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.

Official Title
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Reduced Clavulanate Formulation of Amoxicillin-Clavulanate in Children 6-23 Months With Acute Otitis Media

Conditions
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Acute Otitis Media

Intervention / Treatment
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* Drug: Amoxicillin-Clavulanate potassium


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 6 Months
Maximum Age: 23 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: amoxicillin-clavulanate potassium<br>amoxicillin-clavulanate potassium (600 mg/221.5 mg/5 mL; 28:1) administered prior to February 25, 2016 at 90/3.2 mg/kg/day in two divided doses for 10 days; oral, liquid (formulation 1) or administered as of February 25, 2016 at 80/2.85 mg/kg/day in two divided doses for 10 days; oral, liquid (formulation 2) | Drug: Amoxicillin-Clavulanate potassium<br> <br> * Other names: Augmentin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Distribution of Participants Receiving Formulation 1 for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. Protocol-defined diarrhea is defined as the occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days and is limited to events associated with study product. | Day 1 of administration of amoxicillin-clavulanate until day 12. | 
| The Distribution of Participants Receiving Formulation 2 for Whom Protocol-Defined Diarrhea (PDD) Was Reported and Associated With Study Product | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. Protocol-defined diarrhea is defined as the occurrence of three or more watery stools in 1 day or two watery stools daily for 2 consecutive days and is limited to events associated with study product. | Day 1 of administration of amoxicillin-clavulanate until day 12. | 
| The Distribution of Participants Receiving Formulation 1 for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. Diaper dermatitis is defined as dermatitis in the diaper area calling for prescription of a topical antifungal agent and is limited to events associated with study product. | Day 1 of administration of amoxicillin-clavulanate until day 12. | 
| The Distribution of Participants Receiving Formulation 2 for Whom Diaper Dermatitis Was Reported and Associated With Study Product | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. Diaper dermatitis is defined as dermatitis in the diaper area calling for prescription of a topical antifungal agent and is limited to events associated with study product.. | Day 1 of administration of amoxicillin-clavulanate until day 12. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Distribution of Participants Receiving Formulation 1 Categorized as Treatment Failure (TF) at or Before the End-of-Treatment Visit | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. Treatment failure is defined as substantial persistence or worsening of symptoms specifically attributable to AOM or of otoscopic signs of acute inflammation (bulging of the TM or intense erythema) after 72 hours from the initial AOM, such that additional antimicrobial therapy is deemed advisable. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the TM or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable. | From 72 hours after the initial AOM until the end-of-treatment visit. The mean day for this visit was 14.9. | 
| The Distribution of Participants Receiving Formulation 2 Categorized as Treatment Failure (TF) at or Before the End-of-Treatment Visit | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. Treatment failure is defined as substantial persistence or worsening of symptoms specifically attributable to AOM or of otoscopic signs of acute inflammation (bulging of the TM or intense erythema) after 72 hours from the initial AOM, such that additional antimicrobial therapy is deemed advisable. Clinical success is defined as complete or substantial resolution of symptoms specifically attributable to AOM for 48 hours and of otoscopic signs of acute inflammation (bulging of the TM or intense erythema), with or without persistence of middle-ear effusion, such that no additional antibiotic therapy is deemed advisable. | From 72 hours after the initial AOM until the end-of-treatment visit. The mean day for this visit was 13.9. | 
| 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 | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. An assessment of participants was conducted at the day 7 visit using the AOM-SOS scale. The AOM-SOS scale measures five discrete items: tugging of ears, crying, irritability, difficulty sleeping, and fever. Parents are asked to rate these symptoms in comparison with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Thus, total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. | Day 1 of administration of amoxicillin-clavulanate until the day 7 visit. The mean day for this visit was 7.5. | 
| 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 | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. An assessment of participants was conducted at the day 7 visit using the AOM-SOS scale. The AOM-SOS scale measures five discrete items: tugging of ears, crying, irritability, difficulty sleeping, and fever. Parents are asked to rate these symptoms in comparison with the child's usual state, as none, a little, or a lot, with corresponding scores of 0, 1, and 2. Thus, total scores range from 0 to 10, with higher scores indicating greater severity of symptoms. | Day 1 of administration of amoxicillin-clavulanate until the day 7 visit. The mean day for this visit was 7.6. | 
| The Mean Score Representing the Parent or Guardian's Level of Satisfaction With Therapy for Participants Receiving Formulation 1 | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. The parent or guardian will answer a questionnaire regarding their satisfaction with the therapy their child received. The responses 'very dissatisfied', 'somewhat dissatisfied', 'neither satisfied nor dissatisfied', 'somewhat satisfied' and 'very satisfied' correspond to scores of 1, 2, 3, 4, and 5, respectively. | The end-of-treatment visit. The mean day for this visit was 14.9. | 
| The Mean Score Representing the Parent or Guardian's Level of Satisfaction With Therapy for Participants Receiving Formulation 2 | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. The parent or guardian will answer a questionnaire regarding their satisfaction with the therapy their child received. The responses 'very dissatisfied', 'somewhat dissatisfied', 'neither satisfied nor dissatisfied', 'somewhat satisfied' and 'very satisfied' correspond to scores of 1, 2, 3, 4, and 5, respectively. | The end-of-treatment visit. The mean day for this visit was 13.9. | 
| Distribution of Population Plasma Concentration of Amoxicillin According to Time For Participants Receiving Formulation 1 | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. Plasma concentration of amoxicillin 45 mg/kg/dose was measured. Data points up to 4 hours with a standard deviation of 0 indicate that the assessment was available for only one child. | From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after. | 
| Distribution of Population Plasma Concentration of Amoxicillin According to Time For Participants Receiving Formulation 2 | Participants treated with formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. Plasma concentration of amoxicillin 40 mg/kg/dose was measured. Data points up to 4 hours with a standard deviation of 0 indicate that the assessment was available for only one child. | From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after. | 
| Distribution of Population Plasma Concentration of Clavulanate According to Time For Participants Receiving Formulation 1 | Participants receiving formulation 1 were administered 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 in two divided doses for 10 days. Plasma concentration of clavulanate 1.6 mg/kg/dose was measured. Data points up to 4 hours with a standard deviation of 0 indicate that the assessment was available for only one child. | From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after. | 
| Distribution of Population Plasma Concentration of Clavulanate According to Time For Participants Receiving Formulation 2 | Participants receiving formulation 2 were administered amoxicillin-clavulanate potassium containing a reduced concentration of clavulanate potassium, 600 mg/21.5 mg/5 mL (a ratio of 28:1), administered at 80/2.85 mg/kg/day in two divided doses for 10 days. Plasma concentration of clavulanate 1.425 mg/kg/dose was measured. Data points up to 4 hours with a standard deviation of 0 indicate that the assessment was available for only one child. | From administration of a single dose of amoxicillin-clavulanate until approximately 4 hours after. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ear infections, antibiotics, antibiotic resistance, pediatrics, infants, children, amoxicillin-clavulanate