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Doxepin Hydrochloride in Treating Oral Mucositis Pain in Patients With Head and Neck Cancer Undergoing Radiation Therapy With or Without Chemotherapy

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ClinicalTrials.gov Identifier: NCT01156142
Recruitment Status : Completed
First Posted : July 2, 2010
Results First Posted : May 8, 2017
Last Update Posted : August 9, 2017
Sponsor:
Collaborator:
Information provided by (Responsible Party):

Study Description
Brief Summary:

RATIONALE: Doxepin hydrochloride may be an effective treatment for oral mucositis pain in patients undergoing radiation therapy with or without chemotherapy.

PURPOSE: This randomized phase III trial is studying doxepin hydrochloride to see how well it works compared to placebo in treating oral mucositis pain in patients with head and neck cancer undergoing radiation therapy with or without chemotherapy.


Condition or disease Intervention/treatment Phase
Head and Neck Cancer Mucositis Oral Complications of Radiation Therapy Pain Drug: doxepin hydrochloride Other: placebo Phase 3

Detailed Description:

OUTLINE: This is a multicenter study. Patients are stratified according to gender, concurrent radiosensitizing chemotherapy (yes vs no), and age (< 60 years vs ≥ 60 years). Patients are randomized to 1 of 2 treatment arms.

  • Arm I: Patients receive doxepin hydrochloride oral rinse (swish, gargle, and spit)* over 1 minute on day 1. Patients may crossover to arm II on day 2.
  • Arm II: Patients receive placebo oral rinse (swish, gargle, and spit)* over 1 minute on day 1.

Patients may crossover to arm I on day 2. The primary and secondary objectives are detailed below.

Primary Objective:

Determine whether doxepin oral rinse is effective in reducing OM-related pain in patients undergoing RT to the oral cavity, as measured by a patient-reported questionnaire at 5,15, 30, 60, 120 and 240 minutes

Secondary Objectives:

  1. Assess the adverse event profile of doxepin rinse using a patient-reported questionnaire at 5, 15, 30, 60, 120 and 240 minutes for domains of unpleasant taste, burning or stinging discomfort, and drowsiness.
  2. Compare the incidence of using alternative analgesics before 4 hours, between the doxepin oral rinse and placebo arms.
  3. Assess patient preference for continued therapy with oral rinse after initial test rinse or after the cross-over phase.

NOTE: * Patients are instructed to avoid taking medications for mucositis pain 60 minutes before and after study medication.

After completing study therapy, patients have the option to receive doxepin hydrochloride oral rinse every 4 hours as needed during radiotherapy.

Patients complete questionnaires at baseline, and at 5, 15, 30, 60, 120, and 240 minutes after study medication. Patients who choose to continue doxepin hydrochloride oral rinse also complete weekly questionnaires.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 155 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Supportive Care
Official Title: A Randomized Double-Blind Study of Doxepin Rinse Versus Placebo in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy
Study Start Date : December 2010
Primary Completion Date : May 2012
Study Completion Date : March 2, 2015


Arms and Interventions

Arm Intervention/treatment
Experimental: Arm I
Patients receive doxepin hydrochloride oral rinse (swish, gargle, and spit) over 1 minute on day 1. Patients may crossover to arm II on day 2.
Drug: doxepin hydrochloride
Oral rinse
Placebo Comparator: Arm II
Patients receive placebo oral rinse (swish, gargle, and spit) over 1 minute on day 1. Patients may crossover to arm I on day 2.
Other: placebo
Oral rinse


Outcome Measures

Primary Outcome Measures :
  1. Total Pain Reduction (Mouth and Throat) [ Time Frame: Baseline and Day 1 ]
    The total pain reduction will be calculated by the (average of mouth and throat) area under the curve (AUC) adjusting for baseline, with time scale replaced by a numerical scale of 1,2,3,4,5,6. The numerical scale will be used rather than the raw time scale in order to give proper weights to more immediate patient-reported mouth pain outcomes after treatment. The AUC will be calculated by proration when there are terminal missing data. If the missing data are intermittent, simple imputation will be applied to calculate the AUC. The question ('On a scale from 0 to 10, what number best describes your MOUTH PAIN due to your radiation treatment now?') used 11-point numerical analog scales (0 (no pain) to 10 (worst pain imaginable or possible) scores) to measure pain. The AUCs for the two treatment arms were compared by using the Wilcoxon rank sum test with 95% CIs.


Secondary Outcome Measures :
  1. Total Taste of the Oral Rinse [ Time Frame: Up to 9 days ]
    The total taste of the oral rinse will be calculated by the area under the curve (AUC) adjusting for baseline, with time scale replaced by a numerical scale of 1,2,3,4,5,6 , and analyzed in the same way as the primary endpoint. The numerical scale will be used rather than the raw time scale in order to give proper weights to more immediate patient-reported mouth pain outcomes after treatment. The AUC will be calculated by proration when there are terminal missing data. If the missing data are intermittent, simple imputation will be applied to calculate the AUC. The question ('On a scale from 0 to 10, what number best describes the TASTE OF THE ORAL RINSE now?') used 11-point numerical analog scales (0 (acceptable taste) to 10(terrible taste), with higher values representing worse outcome) to evaluate the total taste of the oral rinse. The AUCs for the two treatment arms were compared by using the Wilcoxon rank sum test with 95% CIs.

  2. Total Stinging or Burning From the Oral Rinse [ Time Frame: Up to 9 days ]
    The total stinging or burning from the oral rinse will be calculated by the area under the curve (AUC) adjusting for baseline, with time scale replaced by a numerical scale of 1,2,3,4,5,6. The numerical scale will be used rather than the raw time scale in order to give proper weights to more immediate patient-reported mouth pain outcomes after treatment. The AUC will be calculated by proration when there are terminal missing data. If the missing data are intermittent, simple imputation will be applied to calculate the AUC. The question ('On a scale from 0 to 10, what number best describes any STINGING OR BURNING FROM THE ORAL RINSE now?') used 11-point numerical analog scales (0 (no stinging or burning) to 10 (worst stinging or burning possible) scores) to total stinging or burning from the oral rinse. The AUCs for the two treatment arms were compared by using the Wilcoxon rank sum test with 95% CIs.The statistical analysis will be the same as the primary analysis.

  3. Total Drowsiness Increase [ Time Frame: Up to 9 days ]
    The total drowsiness increase will be calculated by the area under the curve (AUC) adjusting for baseline, with time scale replaced by a numerical scale of 1,2,3,4,5,6. The numerical scale will be used rather than the raw time scale in order to give proper weights to more immediate patient-reported mouth pain outcomes after treatment. The AUC will be calculated by proration when there are terminal missing data. If the missing data are intermittent, simple imputation will be applied to calculate the AUC. The question ('On a scale from 0 to 10, what number best describes your DROWSINESS now?') used 11-point numerical analog scales (0 (no drowsiness) to 10 (extreme drowsiness, leading to sleep) scores) to measure total drowsiness increase. The AUCs for the two treatment arms were compared by using the Wilcoxon rank sum test with 95% CIs. The statistical analysis will be the same as the primary analysis.

  4. Incidence of Using Alternative Analgesics Between 2 and 4 Hours After the Initial Mouthwash [ Time Frame: Up to 9 days ]
    The incidence of utilizing additional analgesics between 2 and 4 hours after the initial mouthwash will be compared between the arms by the Chi-square test .

  5. Patient Preference for Continuing Therapy With Oral Doxepin Hydrochloride [ Time Frame: Up to 9 days ]
    After each dose was administered, patients were asked if they would like to continue rinses with that particular agent. The percentage of patients who expressed an interest in continuing therapy are reported below.


Eligibility Criteria

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. ≥ 18 years of age
  2. Histologic proof of malignancy currently undergoing a course of RT (with or without chemotherapy) to a dose of ≥ 5000 cGy using 1.60 to 2.20 Gy per fraction. Note: At least one third of the oral cavity mucosa must be included in the radiation therapy fields.
  3. ≥ 4 oral pain felt to be related to mucositis for which the patient wants relief as measured by the Numeric Measure of Oral Pain. Note: An oral exam confirming the presence of mucositis should be performed by the enrolling clinician in addition to patient feedback.
  4. Ability to complete questionnaire(s) independently or with assistance
  5. ECOG Performance Status 0, 1 or 2.
  6. Provide informed written consent.
  7. Willingness to return to enrolling institution for follow-up.

Exclusion Criteria:

  1. Known allergy to doxepin, tricyclic antidepressants, or any known component of the drug formulation
  2. Use of a tricyclic antidepressant or monoamine oxidase inhibitor within the 2 weeks prior to registration
  3. Current untreated or unresolved oral candidiasis or oral HSV infection
  4. Current untreated narrow angle glaucoma
  5. Current untreated urinary retention ≤ 6 weeks prior to registration
  6. Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
  7. Any of the following because this study involves a study agent whose genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are unknown:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01156142


  Hide Study Locations
Locations
United States, Arizona
Mayo Clinic Scottsdale
Scottsdale, Arizona, United States, 85259-5499
United States, Connecticut
Saint Francis/Mount Sinai Regional Cancer Center at Saint Francis Hospital and Medical Center
Hartford, Connecticut, United States, 06105
United States, Florida
Mayo Clinic - Jacksonville
Jacksonville, Florida, United States, 32224
United States, Georgia
MBCCOP - Medical College of Georgia Cancer Center
Augusta, Georgia, United States, 30912
United States, Idaho
Saint Alphonsus Cancer Care Center at Saint Alphonsus Regional Medical Center
Boise, Idaho, United States, 83706
United States, Illinois
CCOP - Carle Cancer Center
Urbana, Illinois, United States, 61801
United States, Indiana
Elkhart Clinic, LLC
Elkhart, Indiana, United States, 46514-2098
Michiana Hematology-Oncology, PC - Elkhart
Elkhart, Indiana, United States, 46514
Elkhart General Hospital
Elkhart, Indiana, United States, 46515
Howard Community Hospital
Kokomo, Indiana, United States, 46904
Center for Cancer Therapy at LaPorte Hospital and Health Services
La Porte, Indiana, United States, 46350
Indiana University Health La Porte Hospital
La Porte, Indiana, United States, 46350
Michiana Hematology-Oncology, PC - South Bend
Mishawaka, Indiana, United States, 46545-1470
Saint Joseph Regional Medical Center
Mishawaka, Indiana, United States, 46545-1470
Michiana Hematology Oncology PC-Mishawaka
Mishawaka, Indiana, United States, 46545
Michiana Hematology Oncology PC - Plymouth
Plymouth, Indiana, United States, 46563
CCOP - Northern Indiana CR Consortium
South Bend, Indiana, United States, 46601
Memorial Hospital of South Bend
South Bend, Indiana, United States, 46601
Michiana Hematology Oncology PC - La Porte
Westville, Indiana, United States, 46391
United States, Iowa
McFarland Clinic, PC
Ames, Iowa, United States, 50010
Cedar Rapids Oncology Associates
Cedar Rapids, Iowa, United States, 52403
Mercy Regional Cancer Center at Mercy Medical Center
Cedar Rapids, Iowa, United States, 52403
United States, Massachusetts
Boston University Cancer Research Center
Boston, Massachusetts, United States, 02118
United States, Michigan
Hickman Cancer Center at Bixby Medical Center
Adrian, Michigan, United States, 49221
Saint Joseph Mercy Cancer Center
Ann Arbor, Michigan, United States, 48106-0995
CCOP - Michigan Cancer Research Consortium
Ann Arbor, Michigan, United States, 48106
Battle Creek Health System Cancer Care Center
Battle Creek, Michigan, United States, 49017
Mecosta County Medical Center
Big Rapids, Michigan, United States, 49307
Oakwood Cancer Center at Oakwood Hospital and Medical Center
Dearborn, Michigan, United States, 48123-2500
Saint John Hospital and Medical Center
Detroit, Michigan, United States, 48236
Genesys Hurley Cancer Institute
Flint, Michigan, United States, 48503
Hurley Medical Center
Flint, Michigan, United States, 48503
Genesys Regional Medical Center
Grand Blanc, Michigan, United States, 48439
Butterworth Hospital at Spectrum Health
Grand Rapids, Michigan, United States, 49503
CCOP - Grand Rapids
Grand Rapids, Michigan, United States, 49503
Lacks Cancer Center at Saint Mary's Health Care
Grand Rapids, Michigan, United States, 49503
Van Elslander Cancer Center at St. John Hospital and Medical Center
Grosse Pointe Woods, Michigan, United States, 48236
Allegiance Health
Jackson, Michigan, United States, 49201
Foote Memorial Hospital
Jackson, Michigan, United States, 49201
Sparrow Regional Cancer Center
Lansing, Michigan, United States, 48912-1811
St. Mary Mercy Hospital
Livonia, Michigan, United States, 48154
Community Cancer Center of Monroe
Monroe, Michigan, United States, 48162
Mercy Memorial Hospital - Monroe
Monroe, Michigan, United States, 48162
Mercy General Health Partners
Muskegon, Michigan, United States, 49444
St. Joseph Mercy Oakland
Pontiac, Michigan, United States, 48341-2985
Mercy Regional Cancer Center at Mercy Hospital
Port Huron, Michigan, United States, 48060
Seton Cancer Institute at Saint Mary's - Saginaw
Saginaw, Michigan, United States, 48601
Lakeland Regional Cancer Care Center - St. Joseph
Saint Joseph, Michigan, United States, 49085
Lakeside Cancer Specialists, PLLC
Saint Joseph, Michigan, United States, 49085
Marie Yeager Cancer Center
Saint Joseph, Michigan, United States, 49085
Munson Medical Center
Traverse City, Michigan, United States, 49684
St. John Macomb Hospital
Warren, Michigan, United States, 48093
United States, Minnesota
MeritCare Bemidji
Bemidji, Minnesota, United States, 56601
Sanford Clinic North-Bemidgi
Bemidji, Minnesota, United States, 56601
Fairview Ridges Hospital
Burnsville, Minnesota, United States, 55337
Mercy and Unity Cancer Center at Mercy Hospital
Coon Rapids, Minnesota, United States, 55433
Fairview Southdale Hospital
Edina, Minnesota, United States, 55435
Mercy and Unity Cancer Center at Unity Hospital
Fridley, Minnesota, United States, 55432
Hutchinson Area Health Care
Hutchinson, Minnesota, United States, 55350
HealthEast Cancer Care at St. John's Hospital
Maplewood, Minnesota, United States, 55109
Minnesota Oncology - Maplewood
Maplewood, Minnesota, United States, 55109
Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
Minneapolis, Minnesota, United States, 55407
Hennepin County Medical Center - Minneapolis
Minneapolis, Minnesota, United States, 55415
New Ulm Medical Center
New Ulm, Minnesota, United States, 56073
Humphrey Cancer Center at North Memorial Outpatient Center
Robbinsdale, Minnesota, United States, 55422-2900
Mayo Clinic Cancer Center
Rochester, Minnesota, United States, 55905
CCOP - Metro-Minnesota
Saint Louis Park, Minnesota, United States, 55416
Park Nicollet Cancer Center
Saint Louis Park, Minnesota, United States, 55416
Regions Hospital Cancer Care Center
Saint Paul, Minnesota, United States, 55101
United Hospital
Saint Paul, Minnesota, United States, 55102
St. Francis Cancer Center at St. Francis Medical Center
Shakopee, Minnesota, United States, 55379
Lakeview Hospital
Stillwater, Minnesota, United States, 55082
Ridgeview Medical Center
Waconia, Minnesota, United States, 55387
Willmar Cancer Center at Rice Memorial Hospital
Willmar, Minnesota, United States, 56201
Minnesota Oncology - Woodbury
Woodbury, Minnesota, United States, 55125
United States, Nebraska
Cancer Resource Center - Lincoln
Lincoln, Nebraska, United States, 68510
CCOP - Missouri Valley Cancer Consortium
Omaha, Nebraska, United States, 68106
Immanuel Medical Center
Omaha, Nebraska, United States, 68122
Alegant Health Cancer Center at Bergan Mercy Medical Center
Omaha, Nebraska, United States, 68124
Lakeside Hospital
Omaha, Nebraska, United States, 68130
Creighton University Medical Center
Omaha, Nebraska, United States, 68131-2197
United States, North Dakota
MeritCare Broadway
Fargo, North Dakota, United States, 58102
Sanford Clinic North-Fargo
Fargo, North Dakota, United States, 58102
CCOP - MeritCare Hospital
Fargo, North Dakota, United States, 58122
Roger Maris Cancer Center at MeritCare Hospital
Fargo, North Dakota, United States, 58122
Sanford Medical Center-Fargo
Fargo, North Dakota, United States, 58122
Altru Cancer Center at Altru Hospital
Grand Forks, North Dakota, United States, 58201
United States, Ohio
Wood County Oncology Center
Bowling Green, Ohio, United States, 43402
Community Cancer Center
Elyria, Ohio, United States, 44035
Hematology Oncology Center
Elyria, Ohio, United States, 44035
Lima Memorial Hospital
Lima, Ohio, United States, 45804
Northwest Ohio Oncology Center
Maumee, Ohio, United States, 43537-1839
St. Charles Mercy Hospital
Oregon, Ohio, United States, 43616
Toledo Clinic - Oregon
Oregon, Ohio, United States, 43616
Flower Hospital Cancer Center
Sylvania, Ohio, United States, 43560
Mercy Hospital of Tiffin
Tiffin, Ohio, United States, 44883
Toledo Hospital
Toledo, Ohio, United States, 43606
St. Vincent Mercy Medical Center
Toledo, Ohio, United States, 43608
Medical University of Ohio Cancer Center
Toledo, Ohio, United States, 43614
CCOP - Toledo Community Hospital
Toledo, Ohio, United States, 43617
St. Anne Mercy Hospital
Toledo, Ohio, United States, 43623
Toledo Clinic, Incorporated - Main Clinic
Toledo, Ohio, United States, 43623
Fulton County Health Center
Wauseon, Ohio, United States, 43567
United States, Virginia
Fredericksburg Oncology, Incorporated
Fredericksburg, Virginia, United States, 22401
United States, Wisconsin
Marshfield Clinic - Chippewa Center
Chippewa Falls, Wisconsin, United States, 54729
Center for Cancer Treatment & Prevention at Sacred Heart Hospital
Eau Claire, Wisconsin, United States, 54701
Marshfield Clinic Cancer Care at Regional Cancer Center
Eau Claire, Wisconsin, United States, 54701
Marshfield Clinic - Ladysmith Center
Ladysmith, Wisconsin, United States, 54848
Marshfield Clinic - Marshfield Center
Marshfield, Wisconsin, United States, 54449
Saint Joseph's Hospital
Marshfield, Wisconsin, United States, 54449
Marshfield Clinic - Lakeland Center
Minocqua, Wisconsin, United States, 54548
Ministry Medical Group at Saint Mary's Hospital
Rhinelander, Wisconsin, United States, 54501
Marshfield Clinic - Indianhead Center
Rice Lake, Wisconsin, United States, 54868
Marshfield Clinic at Saint Michael's Hospital
Stevens Point, Wisconsin, United States, 54481
Saint Michael's Hospital Cancer Center
Stevens Point, Wisconsin, United States, 54481
Marshfield Clinic - Wausau Center
Wausau, Wisconsin, United States, 54401
Diagnostic and Treatment Center
Weston, Wisconsin, United States, 54476
Marshfield Clinic - Weston Center
Weston, Wisconsin, United States, 54476
Ministry Saint Clare's Hospital
Weston, Wisconsin, United States, 54476
Marshfield Clinic - Wisconsin Rapids Center
Wisconsin Rapids, Wisconsin, United States, 54494
Sponsors and Collaborators
Alliance for Clinical Trials in Oncology
National Cancer Institute (NCI)
Investigators
Study Chair: Robert C. Miller, MD Mayo Clinic
More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Alliance for Clinical Trials in Oncology
ClinicalTrials.gov Identifier: NCT01156142     History of Changes
Other Study ID Numbers: NCCTG-N09C6
NCI-2011-02049 ( Registry Identifier: CTRP (Clinical Trials Reporting System) )
CDR0000675520 ( Registry Identifier: PDQ (Physician Data Query) )
U10CA037404 ( U.S. NIH Grant/Contract )
First Posted: July 2, 2010    Key Record Dates
Results First Posted: May 8, 2017
Last Update Posted: August 9, 2017
Last Verified: July 2017

Keywords provided by Alliance for Clinical Trials in Oncology:
oral complications of radiation therapy
mucositis
pain
stage I squamous cell carcinoma of the paranasal sinus and nasal cavity
recurrent squamous cell carcinoma of the hypopharynx
squamous cell carcinoma of the hypopharynx
recurrent squamous cell carcinoma of the larynx
recurrent verrucous carcinoma of the larynx
squamous cell carcinoma of the larynx
verrucous carcinoma of the larynx
recurrent adenoid cystic carcinoma of the oral cavity
recurrent mucoepidermoid carcinoma of the oral cavity
recurrent verrucous carcinoma of the oral cavity
adenoid cystic carcinoma of the oral cavity
mucoepidermoid carcinoma of the oral cavity
verrucous carcinoma of the oral cavity
squamous cell carcinoma of the lip and oral cavity
recurrent basal cell carcinoma of the lip
recurrent squamous cell carcinoma of the lip and oral cavity
basal cell carcinoma of the lip
metastatic squamous neck cancer with occult primary squamous cell carcinoma
recurrent metastatic squamous neck cancer with occult primary
untreated metastatic squamous neck cancer with occult primary
recurrent lymphoepithelioma of the nasopharynx
recurrent squamous cell carcinoma of the nasopharynx
lymphoepithelioma of the nasopharynx
squamous cell carcinoma of the nasopharynx
recurrent lymphoepithelioma of the oropharynx
recurrent squamous cell carcinoma of the oropharynx
lymphoepithelioma of the oropharynx

Additional relevant MeSH terms:
Head and Neck Neoplasms
Mucositis
Stomatitis
Neoplasms by Site
Neoplasms
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Mouth Diseases
Stomatognathic Diseases
Doxepin
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Histamine Antagonists
Histamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs