Doxepin and a Topical Rinse in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy

Study Overview
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Brief Summary
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The purpose of this study is to test whether a mouthwash made with a drug called doxepin can reduce the pain caused by mouth sores resulting from radiation therapy. A number of mouth rinse preparations exist for patients with treatment-related oral mucositis pain such as the DLA rinse, an over-the-counter medication. This study will evaluate the effects of doxepin compared to DLA (diphenhydramine, lidocaine and antacids) and placebo.Doxepin is approved by the Food and Drug Administration (FDA) for the treatment of depression, anxiety, long-term pain management, as well as management of rash.

Detailed Description
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Patients are stratified according to sex (male vs. female), concurrent use of chemotherapy (no vs. yes), patient age at registration (< 60 years old vs. ≥ 60 years old and RTOG acute radiation morbidity criteria (1 vs. 2 vs 3 or more). Protocol therapy will consist of 2 cycles. Patients are randomized to one of three treatment regimens, which include doxepin, DLA and placebo. Cycle One will consist of one day. The care provider or nurse will confirm that the oral pain is at least 4 out of 10 severity level at the time of the rinse on the first day of the study. Patient will be asked to complete the baseline evaluation in the Oral Symptoms booklet. If the pain score is less than 4 then administration will be delayed until the pain is at least 4. Cycle Two will consist of an optional continuation phase lasting up to 7 days. Initiation of the Cycle 2/Continuation Phase may be delayed up to one week after Cycle 1/Day 1. Primary Objective: 1. Determine whether the doxepin rinse or DLA rinse is more effective than placebo in reducing OM-related pain in patients undergoing RT to the oral cavity, as measured by a patient-reported questionnaire at baseline, 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours. Secondary Objectives: Assess the adverse event profile of the doxepin rinse, the DLA rinse agent, and the placebo using a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hour, 2 hours, and 4 hours for domains of unpleasant taste, burning or stinging discomfort, and drowsiness. Compare the incidence of using additional analgesics between 1 and 4 hours after the initial mouthwash, between the doxepin oral rinse, the DLA rinse agent, and the placebo arms. Compare the length of time that each study product is used by patients in the one-week continuation phase. Compare the daily pain scores in the one-week continuation phase for the three study arms. Compare the 24-hour morphine equivalent dose used in the continuation phase for the three study arms.

Official Title
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A Phase III Placebo-Controlled, Randomized Three-Arm Study of Doxepin and a Topical Rinse in the Treatment of Acute Oral Mucositis Pain in Patients Receiving Radiotherapy With or Without Chemotherapy

Conditions
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Acute Oral Mucositis Pain

Intervention / Treatment
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* Drug: doxepin hydrochloride oral solution
* Drug: DLA (diphenhydramine, lidocaine and antacids) rinse
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Documentation of Disease: Histologic documentation of malignancy currently undergoing a course of RT (with or without chemotherapy) including the oral cavity and/or oropharyngeal area to a dose of at least 4500 cGy using more than 5 fractions (i.e., stereotactic body radiation therapy [SBRT] is not allowed). Physical exam demonstrating evidence of radiotherapy-related mucositis in the visible oral cavity and/or oropharynx consistent with mucous membrane toxicity greater than 0 using the Acute Radiation Morbidity Scoring Criteria. At least 4 (out of 10) patient-reported oral pain related to oral mucositis secondary to RT for which the patient seeks relief, as measured on the Oral Pain Assessment. Note: The pain score must be at least 4 at the time that the patient starts the first dose of study medication. The patient may be enrolled to the study if s/he, at times, has a pain score of at least 4, so long as initiation of study treatment begins when the pain score is at least 4. Ability to complete questionnaire(s) by themselves or with assistance. No known allergy to diphenhydramine, lidocaine, antacid (aluminum hydroxide, magnesium hydroxide, and simethicone), doxepin, tricyclic antidepressants, or any known component of the drug formulation in the testing arms. No use of any anti-arrhythmic medication (except for beta-blockers) including lidocaine, linezolid, ipratropium, or medications with high anti-cholinergic potency (including neostigmine, a tricyclic antidepressant or a monoamine oxidase inhibitor) within 2 weeks prior to registration. No current diagnosed untreated or unresolved oral candidiasis or oral HSV infection. No history of untreated narrow angle glaucoma within 6 weeks prior to registration. No untreated urinary retention within 6 weeks prior to registration. No current use of glutamine or sucralfate powders at the time of registration (no washout required). No cryotherapy for prophylactic mucosal protection within 6 weeks prior to registration. Not pregnant, because patients eligible for this study will be receiving radiotherapy, which has known genotoxic, mutagenic and teratogenic effects. Therefore, for women of childbearing potential only, a negative pregnancy test done ≤ 28 days prior to registration is required. Age ≥ 18 years ECOG Performance Status 0, 1, or 2

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: doxepin rinse<br>Patients receive 2.5 mL (25 mg) doxepin and 2.5 mL water orally. Doxepin rinse is administered in the clinic on Day 1 (Cycle 1). There is an optional continuation phase within seven days following Day 1 (Cycle 1), patients will be encouraged to continue treatment with the study agent for an additional week (Cycle 2) where the patient takes the rinse at home every 4 hours. Chemotherapy is allowed during the continuation phase. Patients randomized to doxepin or placebo, they and their caregivers will continue to be blinded to the treatment. Patients will complete the Oral Symptoms booklet per the protocol. | Drug: doxepin hydrochloride oral solution<br>* 2.5 mL (25 mg) doxepin and 2.5 mL water administered orally<br>|
| Active Comparator: DLA (diphenhydramine, lidocaine and antacid) rinse<br>Patients receive 5.0 mL DLA orally. DLA is administered in the clinic on Day 1 (Cycle 1). There is an optional continuation phase within seven days following Day 1 (Cycle 1), patients will be encouraged to continue treatment with the study agent for an additional week (Cycle 2) where the patient takes the rinse at home every 4 hours. Chemotherapy is allowed during the continuation phase. Patients receiving DLA during the continuation phase of the study, they and/or caregivers may be aware that they are receiving DLA. Patients will complete the Oral Symptoms booklet per the protocol. | Drug: DLA (diphenhydramine, lidocaine and antacids) rinse<br>* 5.0 mL administered orally<br>|
| Placebo Comparator: placebo rinse<br>Patients receive 2.5 mL placebo and 2.5 mL water orally. The placebo rinse is administered in the clinic on Day 1 (Cycle 1). There is an optional continuation phase within seven days following Day 1 (Cycle 1), patients will be encouraged to continue treatment with the study agent for an additional week (Cycle 2) where the patient takes the rinse at home every 4 hours. Chemotherapy is allowed during the continuation phase. Patients randomized to doxepin or placebo, they and their caregivers will continue to be blinded to the treatment. Patients will complete the Oral Symptoms booklet per the protocol. | Other: Placebo<br>* 2.5 mL placebo and 2.5 mL water administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Area Under the Curve (AUC) of Total Pain Reduction | Total pain reduction (mouth and throat) was measured by the numerical analogue scale of mouth pain on a scale of 0 to 10, with 0=no pain and 10=worst pain in the questionnaires taken at baseline, and 5, 15, 30, 60, 120, 240 minutes after assigned treatment for doxepin or DLA vs. placebo. The total pain reduction was calculated by the (average of mouth and throat) area under the curve (AUC) adjusting for baseline, with time scale (baseline, 5, 15, 30, 60, 120 and 240 minutes post treatment) replaced by a numerical scale of 0, 1, 2, 3, 4, 5 and 6 respectively. The AUC was prorated when there are terminal missing data. If the missing data were intermittent, simple imputation by trapezoidal rules were applied to calculate the AUC. If a patient cancelled, was missing baseline data, or only provided baseline data, he/she was excluded from the statistical analysis. | Baseline, 5, 15, 30, 60, 120, 240 minutes post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Total Unpleasant Taste of the Oral Rinse as Measured by the Numerical Analogue Scale of Taste of the Oral Rinse in the Questionnaires |  | Up to 4 hours post-treatment | 
| The Total Stinging or Burning From the Oral Rinse as Measured by the Numerical Analogue Scale of Stinging or Burning From the Oral Rinse in the Questionnaires |  | Up to 4 hours post-treatment | 
| The Total Drowsiness Increase as Measured by the Numerical Analogue Scale of Drowsiness Questionnaires |  | Up to 4 hours post-treatment every 4 hours while on treatment | 
| The Incidence of Using Alternative Analgesics Between 1 and 4 Hours After Initial Mouthwash |  | Up to 4 hours post-treatment | 
| Patient Preference for Continued Therapy With Oral Rinse After Initial Test Rinse Phase, as Measured by Item 9 in the Patient-reported Questionnaire After 4 Hours |  | Up to 4 hours post-treatment | 
| The Length of Time in the Continuation Phase |  | Up to 4 hours post-treatment | 
| Pain Score in the Continuation Phase |  | Up to 4 hours post-treatment | 
| Alternative Analgesics Use in the Continuation Phase |  | Up to 4 hours post-treatment |