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The American Academy of Otolaryngology Head and Neck Surgery foundation ventured into Head and Neck Research with SMILE, “An Investigator-Initiated, Multicenter, Randomized, Double-Blind Placebo- Controlled Design study to Assess the Effectiveness of CeviMeline to improve Oral Health in Patients with Xerostomia Secondary to Radiation Therapy for Treatment of Head and Neck Squamous Cell Carcinoma.

Study’’s Significance

Patients who suffer from advanced head and neck squamous cell carcinoma (SCCA) suffer many ups and downs. Their treatment requires aggressive therapy often combining surgical interventions with radiation therapy. Besides surveillance for persistent or recurrent cancer, clinicians seek to help minimize the side effects resulting from these aggressive treatments. Xerostomia or “dry mouth” is often a consequence of radiation treatment (XRT), especially when the XRT fields encompass the parotid glands and submandibular glands bilaterally. Since saliva is essential to normal oral flora and healthy teeth, the lack of saliva in these patients can dramatically and rapidly result in a decline of the patient’s oral health. Dental complications can occur and present significant ongoing medical and surgical problems.

SMILE’s primary objective is to assess the impact of increased salivary flow due to treatment with cevimeline at a dose of 30 mg three times daily compared to placebo in patient reported oral health using the OHIP-49 in subjects with xerostomia secondary to radiation therapy for cancer in the head and neck.

The study drug, cevimeline, marketed as Evoxac® has been revealed to increase salivation in humans and animals. Cevimeline (Evoxac®), distributed by Daiichi-Sankyo Pharmaceutical Corp., is approved by the Federal Drug Administration at a 30mg TID recommended dose for the treatment of dry mouth in patients with Sjogren’s syndrome, an autoimmune disease that causes dry mouth.

Study Design

SMILE was an investigator-initiated, multicenter, randomized, double-blind, placebo-controlled patientoriented outcomes pilot study. Thirteen investigative sites were selected out of 67 BEST ENT sites in the United States. All enrolled adult subjects had clinically significant xerostomia with Grade 1 or 2 xerostomia by CTC version 3.0 criteria.

Patients in the study were given drug (cevimeline or placebo) free of charge and were required to come to two standard of care visits where they were asked to complete two patient information questionnaires, the UW-QOL-HN and OHIP-49 at each visit.

The study was coordinated by the Duke Clinical Research Institute. AAO-HNSF oversight was conducted by the Outcomes Research and Evidence Based Medicine (OREBM) committee and its chair (at the time) Edward Weaver, MD, MPH. Sponsorship was provided by an unrestricted educational grant by Daiichi Sankyo, Inc.

Site Name; Site PI      

Associated Otolaryngologists; Dr. Roger J. Levin
Carle Clinic Association; Dr. Christopher Lansford
Colorado Otolaryngology Associates, PC; Dr. Edward Galloway
Commonwealth Ear, Nose, and Throat; Dr. Donald Welsh
Fauquier ENT Consultants; Dr. Christopher Chang
MD Anderson Cancer Center; Dr. Mark Chambers
Medical College of Georgia; Dr. Christine Gourin
New Mexico Cancer Care Alliance; Dr. Claire Verschraegen
Southwest Cancer Treatment & Research Center; Dr. Carlos Torres
University of Colorado Cancer Center; Dr. Madeleine Kane
University of Iowa; Dr. Douglas J. Van Daele
University of Kansas Medical Center; Dr. Julie Wei
University of Pittsburgh; Dr. Jonas Johnson

CTC v. 3.0 (CTCAE) Xerostomia Criteria

Adverse Event
Dry Mouth/Salivary glands (xerostomia)

Short Name
Dry Mouth

Grade 1
Symptomatic (dry or thick saliva) without significant dietary alteration; unstimulated saliva flow > 0.2 ml/min

Grade 2
Symptomatic and significant oral intake alteration (e.g., copious water, and other lubricants, diet limited to purees and/or soft, moist foods); unstiumulated saliza 0.1 to 0.2 ml/min

Grade 3
Symptoms leading to inability to adequaltey aliment orally; IV fluids, tube feedings, or TPN indicated; unstimulated saliva < 0.1 ml/min

Effectiveness of cevimeline to improve oral health in patients with postradiation xerostomia. Witsell DL, Stinnett S, Chambers MS, Head Neck, 2012 Jan 9, [Epub ahead of print]

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