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

Alliance for Clinical Trials in Oncology

Status and phase: Completed; Phase 3

Conditions: Acute Oral Mucositis Pain

Treatments: Drug: DLA (diphenhydramine, lidocaine and antacids) rinse; Other: Placebo; Drug: doxepin hydrochloride oral solution

Study type: Interventional

Funder types: Other; NIH

Identifiers

NCT02229539

A221304

UG1CA189823 (U.S. NIH Grant/Contract)

NCI-2014-01877 (Registry Identifier)

U10CA037447 (U.S. NIH Grant/Contract)

Details and patient eligibility

About

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.

Full description

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:

1. 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.
2. 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.
3. Compare the length of time that each study product is used by patients in the one-week continuation phase.
4. Compare the daily pain scores in the one-week continuation phase for the three study arms.
5. Compare the 24-hour morphine equivalent dose used in the continuation phase for the three study arms.

Enrollment: 275 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

1. 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).

2. 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.

3. 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.

4. Ability to complete questionnaire(s) by themselves or with assistance.

5. 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.

6. 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.

7. No current diagnosed untreated or unresolved oral candidiasis or oral HSV infection.

8. No history of untreated narrow angle glaucoma within 6 weeks prior to registration.

9. No untreated urinary retention within 6 weeks prior to registration.

10. No current use of glutamine or sucralfate powders at the time of registration (no washout required).

11. No cryotherapy for prophylactic mucosal protection within 6 weeks prior to registration.

12. 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.

13. Age ≥ 18 years

14. ECOG Performance Status 0, 1, or 2

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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275 participants in 3 patient groups, including a placebo group

doxepin rinse

Experimental group

Description:

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.

Treatment:

Drug: doxepin hydrochloride oral solution

DLA (diphenhydramine, lidocaine and antacid) rinse

Active Comparator group

Description:

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.

Treatment:

Drug: DLA (diphenhydramine, lidocaine and antacids) rinse

placebo rinse

Placebo Comparator group

Description:

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.

Treatment:

Other: Placebo