Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit?

• ClinicalTrials.gov Identifier: NCT02554383
• Recruitment Status: Completed
• First Posted: September 18, 2015
• Results First Posted: June 8, 2023
• Last Update Posted: June 29, 2023
• Sponsor: Nader Shaikh
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): Nader Shaikh, University of Pittsburgh

Study Description

Brief Summary:

The objective of this trial is to determine whether certain subgroups of children with acute sinusitis exist in whom antibiotic therapy can be appropriately withheld.

Condition or disease	Intervention/treatment	Phase
Sinusitis; Respiratory Tract Infections	Drug: Amoxicillin-clavulanate; Drug: Placebo	Phase 3

Detailed Description:

The current clinical practice guideline from the American Academy of Pediatrics for the Diagnosis and Management of Acute Bacterial Sinusitis recommends that the diagnosis of acute sinusitis is made when symptoms of an upper respiratory infection (URI) persist beyond 10 days without showing signs of improvement (persistent presentation), when symptoms appear to worsen (on the 6th to 10th day) after a period of improvement (worsening presentation), or when both high fever and purulent nasal discharge are present concurrently for at least 3 consecutive days (severe presentation). In studies to date, children with persistent and worsening presentations comprise >95% of cases. The investigators preliminary data and the available literature suggest that only a subset of children being diagnosed with acute sinusitis on the basis of current criteria are likely to have bacterial disease. This is not entirely surprising because current criteria rely solely on the duration and the quality of respiratory tract symptoms (which are both common and non-specific). Accordingly, it seems likely that many children currently being diagnosed as having acute sinusitis actually have an uncomplicated upper respiratory infection. This is important because acute sinusitis is one of the most common diagnoses for which antimicrobials are prescribed for children in the United States, accounting for 7.9 million prescriptions annually. A critical need thus exists to establish which subgroups of children currently being diagnosed with acute sinusitis actually benefit from antimicrobial therapy.

The objective of this trial is to determine whether certain subgroups of children with acute sinusitis exist in whom antibiotic therapy can be appropriately withheld. This objective will be achieved by conducting a large, randomized, double-blind, placebo-controlled clinical trial in children 2 to 12 years of age with persistent or worsening presentations of acute sinusitis. Based on the investigators preliminary data, the investigators hypothesize that only certain subgroups of children currently being treated for acute sinusitis actually benefit from antimicrobial therapy. By identifying, in a large placebo-controlled trial, subgroups of children who respectively do and do not benefit from antimicrobial therapy, the investigators will be better able to determine which children should be classified as having acute bacterial sinusitis. Accordingly, the results of this trial may impact not only the treatment guidelines for acute sinusitis but also the diagnostic criteria, and will help ensure that, to the extent possible, antibiotic use is limited to appropriate patients. This, in turn, will maximize the likelihood of achieving optimal outcomes and minimize the risk of promoting antibiotic resistance.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 515 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Efficacy of Antibiotics in Children With Acute Sinusitis: Which Subgroups Benefit?
• Actual Study Start Date: February 2016
• Actual Primary Completion Date: March 31, 2022
• Actual Study Completion Date: March 9, 2023

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Treatment A; Amoxicillin-clavulanate (90/6.4 mg/kg/d in 2 divided dosed for 10 days)	Drug: Amoxicillin-clavulanate; Amoxicillin-clavulanate (90/6.4 mg/kg/d in 2 divided dosed for 10 days); Other Name: Augmentin-Extra strength
Placebo Comparator: Treatment B; Placebo made to match the study antibiotic will be taken bid orally for 10 days	Drug: Placebo; placebo made to match the study antibiotic given twice a day orally for 10 days

Outcome Measures

Primary Outcome Measures :

1. The Mean Pediatric Rhinosinusitis Symptom Scale (PRSS) Score Over the First 10 Days of Follow-up According to the Presence of Pathogens in the Nasopharynx at Enrollment [ Time Frame: Days 2 to 11 ]
   The Pediatric Rhinosinusitis Symptom Scale (PRSS) is a 8 item scale assessing symptoms of sinusitis. Parents are asked how their child has been doing over the last 24 hours by rating each of 8 symptoms - stuffy nose, runny nose, daytime cough, tiredness, irritability, trouble breathing through the nose, nighttime cough & trouble sleeping - as none, almost none, a little, some, a lot & an extreme amount with respective scores of 0, 1, 2, 3, 4 & 5. The 8 ratings were summed to obtain a PRSS score. Scores ranged from 0-40. Higher scores indicate greater severity. The parent completed the scale on Day 1 (enrollment) & electronically on diaries evenings Days 2-11. Pathogens cultured were Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis.
2. The Mean Pediatric Rhinosinusitis Symptom Scale (PRSS) Score Over the First 10 Days of Follow-up According to the Presence of Colored Nasal Discharge at Enrollment [ Time Frame: Days 2 to 11 ]
   The Pediatric Rhinosinusitis Symptom Scale (PRSS) is a 8 item scale assessing symptoms of sinusitis. Parents are asked how their child has been doing over the last 24 hours by rating each of 8 symptoms - stuffy nose, runny nose, daytime cough, tiredness, irritability, trouble breathing through the nose, nighttime cough & trouble sleeping - as none, almost none, a little, some, a lot & an extreme amount with respective scores of 0, 1, 2, 3, 4 & 5. The 8 ratings were summed to obtain a PRSS score. Scores ranged from 0-40. Higher scores indicate greater severity. The parent completed the scale on Day 1 (enrollment) & electronically on diaries evenings Days 2-11. Nasal discharge, either yellow or green, was considered colored.

Secondary Outcome Measures :

1. The Distribution of Children Experiencing Treatment Failure (TF) [ Time Frame: Day of enrollment to the day of the follow-up visit. The mean length of actual follow-up was 13.4 days. For each child with incomplete follow-up, multiple imputation was used and PRSS scores for the remaining days were imputed. ]
   The Pediatric Rhinosinusitis Symptom Scale (PRSS) is a 8 item scale assessing symptoms of sinusitis. Parents are asked how their child has been doing over the last 24 hours by rating each of 8 symptoms - stuffy nose, runny nose, daytime cough, tiredness, irritability, trouble breathing through the nose, nighttime cough & trouble sleeping - as none, almost none, a little, some, a lot & an extreme amount with respective scores of 0, 1, 2, 3, 4 & 5. The 8 ratings were summed to obtain a PRSS score. Scores ranged from 0-40. Higher scores indicate greater severity. The parent completed the scale on Day 1 (enrollment), electronically evenings Days 2-11 & at the follow-up visit. If, compared to the Day 1 score, there was >20% increase at any time, decrease <2 on Day 3, <20% decrease on Day 4, <20% decrease on 2 consecutive occasions Days 5-11 or <50% decrease at follow-up, then criterion for treatment failure (TF) was met. Multiple imputation was used when data was insufficient to assess TF.
2. The Distribution of Children Developing Acute Otitis Media (AOM) Over the First 10 Days of Follow-up [ Time Frame: Days 2 to 11, where Day 1 is day of enrollment. The mean number of days of follow-up in this interval was 9.8. ]
   AOM is an infection of the middle ear marked by acute symptoms and a bulging tympanic membrane. Its diagnosis coincided with receipt of a systemic antibiotic. Systemic antibiotics include Amoxicillin, Amoxicillin-clavulanate, Azithromycin, Bacillin L-A, Cefdinir, Clindamycin, Doxycycline, Levofloxacin, Ofloxacin & Sulfamethoxazole-Trimethoprim. Start and stop dates were recorded.
3. The Distribution of Children Receiving a Systemic Antibiotic Over the First 10 Days of Follow-up [ Time Frame: Days 2 to 11, where Day 1 is day of enrollment. The mean number of days of follow-up in this interval was 9.8. ]
   Systemic antibiotics include Amoxicillin, Amoxicillin-clavulanate, Azithromycin, Bacillin L-A, Cefdinir, Clindamycin, Doxycycline, Levofloxacin, Ofloxacin & Sulfamethoxazole-Trimethoprim. Start and stop dates were recorded. The antibiotic received is exclusive of the study product assigned at enrollment.
4. The Distribution of Children for Whom Diarrhea or Generalized Rash Was Reported [ Time Frame: Day 1 through Day 23. ]
   The monitoring of adverse events (AEs), i.e. diarrhea or generalized rash, began on Day 1 (enrollment) and continued through Day 23 (the follow-up visit). Diarrhea was the occurrence of 3 or more watery stools on one day or 2 watery stools on each of 2 consecutive days. Parents recorded in daily diaries, Days 1-11, information regarding the occurrence of diarrhea. Additionally, parents were asked at the follow-up visit if their child had diarrhea while on study product.
5. The Distribution of Children Compliant With Study Medication [ Time Frame: Days 1 to 11, where Day 1 is day of enrollment ]
   Compliance, expressed as a percentage, is the total number of doses taken divided by the total number of expected doses. The child is considered compliant if he/she has received at least 70% of the study medication. The parent completed diaries evenings Days 2-11. The diaries included yes/no questions - (1) did your child take the study medication last night and (2) did your child take the study medication this morning? The total number of doses taken was calculated based on the responses to question (1), and accounted for the dose dispensed at enrollment when enrollment was 1pm or earlier on Day 1. The total of expected doses was determined from the responses to questions (1) and (2), and accounted for scenarios in which the child was taken off the study medication by the clinician. In some cases, due to incomplete diaries the information was insufficient to declare a child either compliant or not compliant.

Other Outcome Measures:

1. The Distribution of Children With a Nonsusceptible Pathogen at the Follow-up Visit [ Time Frame: The follow-up visit. The mean number of days from enrollment to the follow-up visit was 13.4. ]
   The nonsusceptible pathogens considered are penicillin-intermediate and penicillin-resistant Streptococcus pneumoniae (SPN) and ß-lactamase-positive Haemophilus influenzae (NTHi). Susceptibility to penicillin was defined as follows: susceptible as a minimum inhibitory concentration (MIC) of <=0.06 μg/mL; intermediate as an MIC of greater than 0.06 to less than 2 μg/mL; and resistant as an MIC of >=2 μg/mL. A nasopharyngeal specimen for bacterial culture was obtained at the time of the follow-up visit, occurring between study days 11 and 23.

Eligibility Criteria

• Ages Eligible for Study: 2 Years to 11 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Meets criteria for "persistent" or "worsening" presentations of sinusitis
• Baseline score ≥9 on the Pediatric Rhinosinusitis Symptom Scale

Exclusion Criteria:

• Severe presentation (≥3 days of colored nasal discharge and fever ≥39°C
• Asthma/allergic rhinitis explains symptoms
• Allergy to amoxicillin-clavulanate
• Immotile cilia syndrome
• Cystic fibrosis
• Immunodeficiency
• Parental inability to read/write English or Spanish
• Other concurrent infection (e.g., pneumonia, acute otitis media, streptococcal pharyngitis)
• Systemic toxicity
• Wheezing on exam
• Antibiotic use within 15 days

Contacts and Locations

Locations

United States, Kentucky

Kentucky Pediatric/Adult Research

Bardstown, Kentucky, United States, 40004

United States, Oregon

Cyn3rgy Research

Gresham, Oregon, United States, 97030

United States, Pennsylvania

The Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

UPMC Children's Hospital of Pittsburgh

Pittsburgh, Pennsylvania, United States, 15224

United States, West Virginia

WVU Medicine Pediatric and Adolescent Group Practice

Morgantown, West Virginia, United States, 26501

United States, Wisconsin

American Family Children's Hospital

Madison, Wisconsin, United States, 53792

Sponsors and Collaborators

Nader Shaikh

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Nader Shaikh, MPH, MD; University of Pittsburgh
• Principal Investigator: Ellen R Wald, MD; University of Wisconsin, American Family Children's Hospital

  Study Documents (Full-Text)

Documents provided by Nader Shaikh, University of Pittsburgh:

Study Protocol and Statistical Analysis Plan  [PDF] November 2, 2021

More Information

• Responsible Party: Nader Shaikh, Associate Professor of Pediatrics, University of Pittsburgh School of Medicine, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT02554383
• Other Study ID Numbers: STUDY20110386; U01AI118506 ( U.S. NIH Grant/Contract )
• First Posted: September 18, 2015
• Results First Posted: June 8, 2023
• Last Update Posted: June 29, 2023
• Last Verified: June 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes

Keywords provided by Nader Shaikh, University of Pittsburgh:

pediatrics; antibiotics; placebo

Additional relevant MeSH terms:

Respiratory Tract Infections; Sinusitis; Infections; Respiratory Tract Diseases; Paranasal Sinus Diseases; Nose Diseases; Otorhinolaryngologic Diseases; Amoxicillin; Clavulanic Acid; Clavulanic Acids; Amoxicillin-Potassium Clavulanate Combination; Anti-Bacterial Agents; Anti-Infective Agents; beta-Lactamase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action