N-Acetylcysteine as an Adjunct for Refractory Chronic Suppurative Otitis Media

November 29, 2019 updated by: Dr Brian Westerberg, St. Paul's Hospital, Canada
Chronic suppurative otitis media (CSOM) can be particularly difficult to treat as a number of patients do not respond to routine antibiotic or surgical treatments. The current treatment involves administering combination antibiotic anti-inflammatory ear drops such as Ciprodex (ciprofloxacin 0.3% / dexamethasone 0.1%). Although most patients experience a relief of symptoms, a fraction of patients remain refractory to treatment. Recent findings suggest that the addition of N-acetylcysteine (0.5-2%) to Ciprodex is a superior treatment for otitis media with effusion compared to the use of Ciprodex alone.

Study Overview

Status

Withdrawn

Conditions

Intervention / Treatment

Detailed Description

Chronic suppurative otitis media (CSOM) is the presence of symptoms, signs, and physical findings that can result in long-term damage to the middle ear as a result of infection or inflammation. The condition is defined as chronic drainage from the ear, lasting longer than 12 weeks, through a perforated tympanic membrane. Although the pathogenesis may result from the actions of inflammatory mediators and cytokines released following an infection, recent evidence also suggests that biofilm formation may be responsible for sustaining the inflammatory response that promotes the persistent effusion (1). These patients present a challenge to otolaryngologists because a number do not respond to typical oral and topical antibiotics.

N-acetylcysteine (NAC) is an antioxidant commonly used in the treatment of acetaminophen overdose, and has well documented mucolytic properties. In vitro, NAC has been shown to significantly inhibit the formation of bacterial biofilms when used alone or enhance the antimicrobial effects of other drugs such as ciprofloxacin (3), fosfomycin and tigecycline when used in combination (4-6). The application of NAC to the middle ear in patients with tympanostomy tubes has been shown to increase tube longevity, and decrease the replacement of tubes, recurrence of infection, tympanosclerosis, and subsequent physician visits (7). Recent findings from a case series suggest that the addition of N-acetylcysteine (NAC) to Ciprodex otic solution is a superior treatment for chronic otitis media compared to Ciprodex alone (3). Although the practice of supplementing Ciprodex otic solution, a standard pharmacologic treatment for otitis media, with NAC in order to treat patients with difficult infections holds therapeutic promise, the efficacy of the treatment has not been objectively assessed in a controlled study to date in a patient population of adequate size.

The purpose of this study will be to assess the efficacy of Ciprodex augmented with NAC compared to Ciprodex alone in a blinded study in subjects for whom other therapies for a chronically draining ear have been ineffective.

Hypothesis:

The cessation of otorrhea is expected to be achieved in a greater number of subjects with otorrhea treated with Ciprodex otic solution supplemented with NAC compared to Ciprodex alone. We expect that patients treated with Ciprodex augmented with NAC will experience an earlier cessation of symptoms and a longer duration of complete response following treatment.

Justification:

The current pharmacologic treatment for CSOM involves combination antibiotic anti-inflammatory otic drops. Ciprodex (ciprofloxacin 0.3% / dexamethasone 0.1%) has been shown to be safe and effective in both children and adults with ear infections. Although most patients experience a relief of symptoms, clinical data from various studies show 10-15% patients do not respond to treatment (2). Recent findings suggest that the addition of N-acetylcysteine (NAC) to Ciprodex otic solution is a superior treatment for chronic otitis media compared to Ciprodex alone (3).

Objectives:

The specific aim of this project is to compare the effect of Ciprodex otic solution alone with the use of Ciprodex augmented with 1.25% NAC in a randomized double-blind trial.

Research Method:

Patients who have experienced at least 1 month of continuous daily otorrhea despite treatment will be recruited from tertiary otology/neurotology clinics. Patient information, including previous failed interventions, duration of otorrhea, baseline audiometry, and existing medical conditions will be documented prior to initiating treatment.

Subjects will be randomly assigned to one of the two treatment groups and instructed to administer 3 drops three times daily in the affected ear for 14 days. One group will use standard Ciprodex solution; the second group will use Ciprodex to which 0.5mL of 20% NAC was added to the 7.5mL bottle (final concentration 1.25%)

Follow-up visits will be scheduled in 2 week intervals, where patients will undergo audiometry re-assessment and treatment progress will be monitored by history and binocular microscopy. Compliance to treatment will be confirmed during follow-up visits and patients will be provided fresh otic solution for a further 14 days if the discharge persists, to a maximum duration of therapy of 8 weeks. During this period patients will be assessed every 2 weeks, as is currently the standard treatment. Potential adverse reactions such as otalgia, tinnitus, ear fullness, or vertigo will also be documented at each visit. After a maximum of 8 weeks of treatment, patients who continue to experience otorrhea will undergo alternative treatment regimens which may include oral or topical antibiotics, or surgery. Patients who have been successfully treated will be monitored at 4 to 6 months to assess whether a complete and durable cessation of otorrhea has been achieved.

Randomization of the drugs will be performed by the hospital site pharmacists prior to dispensing the solution to subjects. Random number lists will be generated and randomization performed in blocks of 4 through the St. Paul's Hospital Pharmacy. The Principle Investigator will have access to the database should an emergency situation arise.

Statistical Analysis:

Statistical analysis including two-tailed paired Student's t tests will be performed to compare the treatment duration required before patients experience a cessation of otorrhea for each of the two treatment groups. Thirty patients (15 per treatment group) are expected to be recruited for this study.

Study Type

Interventional

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V6Z 1Y6
        • St. Paul's Hospital BC Rotary Hearing & Balance Centre

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • continuous otorrhea for a duration of greater than 6 months
  • at least 2 previous treatment regimes for otitis media, which may include topical or oral antibiotics, myringotomy or tympanostomy, and surgery

Exclusion Criteria:

  • existing cholesteatoma
  • known allergy to ciprofloxacin, dexamethasone, or N-acetylcysteine
  • patients who are unlikely to adhere to the treatment regime and follow-up visits

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Ciprodex otic solution
ciprofloxacin 0.3% / dexamethasone 0.1% otic solution
Drug: Ciprodex
Administer 3 to 5 drops tid for 14 days. Continue treatment for another 14 days if otorrhea persists.
Other Names:
  • ciprofloxacin 0.3% / dexamethasone 0.1%
Experimental: Ciprodex with 2% NAC
Ciprodex otic solution (ciprofloxacin 0.3% / dexamethasone 0.1%) augmented with 2% N-acetylcysteine
Drug: Ciprodex and 2% NAC
Administer 3 to 5 drops tid for 14 days. Continue treatment for another 14 days if otorrhea persists.
Other Names:
  • Ciprodex with 2% N-Acetylcysteine

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
cessation of otorrhea
Time Frame: 4 weeks
4 weeks

Secondary Outcome Measures

Outcome Measure
Time Frame
durable cessation of otorrhea
Time Frame: 18 months
18 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

St. Paul's Hospital, Canada

Investigators

  • Principal Investigator: Brian D Westerberg, MD, St. Paul's Hospital Rotary Hearing Clinic

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 29, 2019

Primary Completion (Actual)

November 29, 2019

Study Completion (Actual)

November 29, 2019

Study Registration Dates

First Submitted

August 7, 2009

First Submitted That Met QC Criteria

August 10, 2009

First Posted (Estimate)

August 11, 2009

Study Record Updates

Last Update Posted (Actual)

December 3, 2019

Last Update Submitted That Met QC Criteria

November 29, 2019

Last Verified

November 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • H09-00953

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

No

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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