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National Institute on Deafness and
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Tuesday, October 7, 2003
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Methotrexate Not Effective in Maintaining Improvements in Hearing Gained from Prednisone

Bethesda, Maryland — Methotrexate is not effective in maintaining hearing in patients with autoimmune inner ear disease (AIED) who had been previously treated with prednisone, according to the results of a multi-center study funded by the National Institute on Deafness and Other Communication Disorders (NIDCD), one of the National Institutes of Health (NIH). The study, published in the October 8 issue of the Journal of the American Medical Association, was carried out by the Otolaryngology Clinical Trials Cooperative Group under the auspices of the American Academy of Otolaryngology-Head and Neck Surgery Foundation.

AIED is a rare disorder that can result in rapidly progressive hearing loss and deafness if left untreated. Because evidence suggests that an altered immune response may play a role in its development, therapy that targets the immune system is considered the standard of treatment for AIED. A number of treatments have been proposed for long-term management of AIED, but lack scientific validation.

High-dose prednisone is known to reverse hearing loss and maintain hearing, but usually cannot be given for long periods of time. Prednisone in combination with other drugs has been proposed as an effective approach to long-term management of hearing loss due to AIED. Cytotoxic drugs were initially considered but many of these agents can have serious side effects that may result in unacceptable long-term risks, especially in young people.

Methotrexate has been shown to improve hearing and balance in Meniere’s disease and other hearing disorders and is generally considered safer and better tolerated than cytotoxic drugs. Evidence from small, uncontrolled studies suggested that methotrexate might be helpful in treating AIED. A randomized, controlled study was needed to determine the drug’s potential to maintain hearing achieved with prednisone therapy.

Participants for the study were recruited at 10 tertiary care centers around the country.* A prospective, double-blind placebo controlled study was conducted with 67 AIED patients who reported progressive loss of hearing in at least one ear and whose hearing improved after one month of receiving high-dose prednisone.

“This clinical trial, under the leadership of Jeffrey P. Harris, M.D., Ph.D., of the University of San Diego, was undertaken to provide clinicians with important evidence-based guidance for the use of potentially toxic medications to treat patients with AIED,” said Patrick E. Brookhouser, M.D., Principal Investigator of the Otolaryngology Clinical Trials Cooperative Group.

Study participants were randomized to receive either methotrexate or placebo, while prednisone was slowly tapered in both groups. Final hearing assessment was carried out at 52 weeks to determine each participant’s hearing level.

The researchers found that patients in both the methotrexate and placebo groups had similar rates of hearing loss. No significant differences were noted in the two groups with respect to standard measurements of hearing, i.e. pure tone air conduction thresholds and word identification scores.

“This randomized, controlled clinical trial demonstrates that methotrexate is no more effective than placebo in maintaining hearing improvements in patients with AIED who had initial benefit from high-dose corticosteroids,” said James F. Battey, Jr., M.D., Ph.D., director of the NIDCD. “Recruitment into the study was halted as soon as it became apparent that hearing loss was comparable in both groups.”

Dr. Battey adds, “The results of this study clearly underscore the need for more effective and less toxic therapy for AIED, and that randomized, controlled clinical trials are necessary to establish benefit.”

NIDCD supports and conducts research and research training on the normal and disordered processes of hearing, balance, smell, taste, voice, speech, and language and provides health information, based upon scientific discovery, to the public. For more information on NIDCD programs: www.nidcd.nih.gov.

The American Academy of Otolaryngology-Head and Neck Surgery (www.entnet.org) represents the nation’s specialist-physicians who diagnose and treat disorders of the ear, nose, and throat and related structures of the head and neck.

For more information on the study, contact:

A. Julianna Gulya, M.D., Chief, Clinical Trials, Epidemiology and Biostatistics Branch, National Institute on Deafness and Other Communication Disorders, Bethesda, Maryland; 301-435-4085.

Jeffrey P. Harris, M.D., Ph.D., Principal Investigator, AIED Clinical Trial, Division of Otolaryngology-Head and Neck Surgery, University of California, San Diego; 619-543-7896.

Patrick E. Brookhouser, M.D., Principal Investigator, Otolaryngology Clinical Trials Cooperative Group, Boys Town National Research Hospital, Omaha, Nebraska; 402-498-6510.

Maureen Hannley, Ph.D., Associate Vice President for Research and Development, American Academy of Otolaryngology-Head and Neck Surgery, Alexandria, Virginia; 703-519-1547.


Study Statistician

Mark Espeland, Ph.D., P.I. Study Statistician, Clinical Trials Coordinating Committee, Wake Forest University Medical Center, Winston-Salem, North Carolina.

*Participating Clinical Centers

Cleveland Clinic Foundation: Gordon B. Hughes, M.D. (Co-Investigator).

House Ear Institute: Jennifer M. Derebery, M.D. (Co-Investigator); Ralph A. Nelson, M.D.

Johns Hopkins University: John K. Niparko, M.D. (Co-Principal Investigator)

Massachusetts Eye and Ear Infirmary: Richard Moscicki, M.D. (Co-Principal Investigator); Steven D. Rauch, M.D.

New York University: Paul E. Hammerschlag, M.D. (Co-Principal Investigator)

University of California, San Diego: Jeffrey P. Harris, M.D., Ph.D. (Principal Investigator, Steering Committee Chair)

University of Iowa: Bruce J. Gantz, M.D. (Co-Principal Investigator)

University of Miami: Thomas J. Balkany, M.D. (Co-Principal Investigator)

University of Michigan: Steven A. Telian, M.D. (Co-Principal Investigator)

University of Texas-Southwestern, Dallas: Peter S. Roland, M.D. (Co-Principal Investigator)


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