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Symptoms and General Pathology

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Esophageal Neoplasms

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Carcinoma, Non-Small-Cell Lung

Thyroid Neoplasms

Thyroid Diseases

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Pain

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Thymoma

Thymus Neoplasms

Esophagitis

Neoplasms, Second Primary

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adenoma

Neoplasms, Mesothelial

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

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Bronchial Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Head and Neck Neoplasms

Gastrointestinal Diseases

Esophageal Diseases

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Endocrine System Diseases

Esophageal Cancer

Small Cell Lung Cancer

Soft Tissue Sarcoma

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Pharmaceutical Solutions

All Drugs and Chemicals

Central Nervous System Depressants

Psychotropic Drugs

Anti-Allergic Agents

Antiemetics

Gastrointestinal Agents

Dermatologic Agents

Doxepin

Diphenhydramine

Promethazine

Hypnotics and Sedatives

Antidepressive Agents

Antidepressive Agents, Tricyclic

Histamine Antagonists

Histamine

Histamine phosphate

Neurotransmitter Agents

Patients receive doxepin hydrochloride oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm II on day 3.

Patients receive placebo oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm I on day 3.

Doxepin Hydrochloride

Placebo

Quality-of-Life Assessment

Questionnaire Administration

Terence Sio

This randomized pilot clinical trial studies the effects of taking doxepin hydrochloride as compared to placebo (inactive drug) in treating esophageal pain in patients with cancer located in the chest area receiving radiation therapy to the thorax with or without chemotherapy. Doxepin hydrochloride is a tricyclic antidepressant drug which was recently shown to be helpful for mouth pain in patients receiving radiation therapy. Doxepin hydrochloride affects the surface of the esophagus, which may be helpful in reducing the pain caused by radiation therapy.

PRIMARY OBJECTIVES:

I. To provide baseline data regarding the effectiveness of doxepin (doxepin hydrochloride) in reducing esophagitis-related pain in patients undergoing radiation therapy (RT) to the thorax, as measured by a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hour and then at 2 and 4 hours on day 1.

SECONDARY OBJECTIVES:

I. To assess the adverse event profile of doxepin swish and swallow using a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hour and then at 2 and 4 hours using Common Terminology Criteria for Adverse Events (CTCAE) and Radiation Therapy Oncology Group (RTOG) acute toxicity criteria, and also for domains of unpleasant taste, burning/stinging discomfort, and drowsiness.

II. To evaluate the effectiveness of doxepin in reducing esophagitis-related pain in patients undergoing RT to the thorax, as measured by a patient-reported questionnaire at 5 minutes, 15 minutes, 30 minutes, 1 hours and then at 2 and 4 hours on days 1 and 3 (including the cross-over phase).

III. To compare and provide baseline data regarding alternative analgesic use between the doxepin and placebo arms.

IV. To provide baseline data regarding the patients? preference for continued therapy with doxepin or placebo after initial test dose or after the cross-over phase, as measured by items 9 and 10 in the patient-reported questionnaire at 4 hours after administration of the study medication and the actual participation rate.

TERTIARY OBJECTIVES:

I. To assess pain reduction and other adverse event profile in the optional continuation phase of doxepin oral rinse therapy. (Only applies to patients who have the optional continuation of doxepin oral rinse after the first two phases)

OUTLINE: Patients are randomized to 1 of 2 treatment groups.

GROUP I: Patients receive doxepin hydrochloride oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm II on day 3.

GROUP II: Patients receive placebo oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1. Patients then crossover to Arm I on day 3.

In both arms, patients may continue to receive doxepin hydrochloride oral solution every 4 hours as needed during radiation therapy.

Doxepin Hydrochloride in Treating Esophageal Pain in Patients With Thoracic Cancer Receiving Radiation Therapy to the Thorax With or Without Chemotherapy

A Pilot, Double-Blind, Randomized, Two-Arm Crossover Study of Doxepin Versus Placebo for Esophagitis-Induced Pain in Patients Receiving Radiotherapy to the Thorax With or Without Chemotherapy

Means and proportions, along with 95% confidence intervals and plots over time will be reported for adverse event levels by week.

Means and proportions, along with 95% confidence intervals and plots over time will be reported for pain levels by week.

Comparative statistics will be used to explore the relationship between quality of life and radiation-induced thoracic toxicities. These analyses will include scatterplots, spearman correlations, t-tests and chi-square tests.

Average Area Under the Curve per assessment (aAUCpa) of pain for the first cycle of treatment. Scores are reported on a 0-100 scale, where 100=better outcome QOL. The aAUCpa is the average of each AUC between each sequential assessment. Patients will assess their pain at baseline and at 5, 15, 30, 60, 120, and 240 minutes after treatment. The AUC calculation is based on the assessment number (1,2,3,4,5,6) instead of the actual number of minutes (5,15,30,60,120,240). This results in an AUC measure that is the average pain score across all of the measurements and is not a function of the number of minutes from treatment. The area under the curve of these 6 time points will be adjusted by their baseline pain score. The pain scores at each time point are given equal weights in the AUC calculation and the AUC calculation does not use the number of minutes after treatment. Therefore, the AUC measurement scale is the same as the original pain score scale.

Incidence of any grade 3 or higher adverse events using Common Terminology Criteria for Adverse Events (CTCAE). Number or patients reporting a grade 3 or higher adverse event according to CTCAE

Subgroup analyses will be performed to determine differential effects within the two stratification factors.

National Cancer Institute (NCI)

Mayo Clinic

Since only one patient was accrued and completed the study on one arm, patient confidentiality prevents the reporting of results per intervention. Therefore, the study results are only reported for the first study period (before crossover) and only for a single intervention (placebo).Serious AE (SAE) reports may include any serious or non-serious events considered related to the primary event; collectively, these events are referred to as Expedited AEs, \& appear in the SAE table.

Patients receive placebo oral solution (swish, gargle for 30 seconds, and slowly swallow) on day 1.

Age, Continuous

Sex: Female, Male

5 were accrued but only 3 provided data. Since only 1 patient was accrued \& completed the study on 1 arm, patient confidentiality prevents the reporting of results per intervention. 2nd crossover was optional; none chose to crossover. The study results are only reported for the 1st study period (before crossover) \& only for placebo intervention.

Terence T. Sio, MD, MS

Patient #1

Patient #2

Patient #3

Change in Mouth Pain as Measured by Average Area Under the Curve Per Assessment

Incidence of Any Grade 3 or Higher Adverse Events Using Common Terminology Criteria for Adverse Events (CTCAE)

Only patients who submitted data on alternative analgesics are evaluable for this outcome measure. None of the patients provided information about alternative analgesics, so this secondary outcome could not be analyzed.

Use of Alternative Analgesics

Only patients who submitted data on patient preference are evaluable for this outcome measure. Since none of the patients crossed over to the optional phase of the study, this secondary outcome could not be analyzed.

Patient Preference for Continued Therapy at Initial Dose and Crossover

Incidence of Adverse Events Graded According to Common Terminology Criteria for Adverse Events, Radiation Therapy Oncology Group, and Patient Reported Outcomes (Continuation Phase)

Pain Levels (Continuation Phase)

Quality of Life Using European Organization for Research and Treatment of Cancer Quality of Life-Lung Cancer 13 and Functional Assessment of Cancer Therapy-Lung

Overall Study

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Nervous System Diseases

Nasopharyngeal Carcinoma

Recurrence

Adenocarcinoma

Carcinoma, Squamous Cell

Papilloma

Carcinoma, Basal Cell

Stomatitis

Mucositis

Granuloma

Carcinoma, Adenoid Cystic

Laryngeal Diseases

Esthesioneuroblastoma, Olfactory

Carcinoma, Acinar Cell

Carcinoma, Verrucous

Papilloma, Inverted

Carcinoma, Mucoepidermoid

Mucoepidermoid Tumor

Gastroenteritis

Mouth Diseases

Stomatognathic Diseases

Acute Graft Versus Host Disease

Adenoid Cystic Carcinoma

Olfactory Neuroblastoma

Tongue Cancer

Acinic Cell Carcinoma

Mucoepidermoid Carcinoma

Metastatic Squamous Neck Cancer With Occult Primary

Midline Lethal Granuloma

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.

Patients receive placebo oral rinse (swish, gargle, and spit) over 1 minute on day 1. Patients may crossover to arm I on day 2.

doxepin hydrochloride

placebo

Robert C. Miller, MD

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.

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.

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

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

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.

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.

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.

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.

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 .

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.

Alliance for Clinical Trials in Oncology

The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for AE reporting. All graded adverse events are reported.

Patients receive (10 mg/mL x 2.5 mL) 25 mg doxepin hydrochloride (diluted to 5 mL with 2.5 mL of sterile water for irrigation, or sterile water for injection, or distilled water) oral rinse (swish, gargle, and spit) over 1 minute on day 1. Patients may crossover to arm II on day 2.

Arm I (Doxepin-Placebo)

Patients receive 2.5 mL placebo (diluted to 5 mL with 2.5 mL of sterile water for irrigation, or sterile water for injection, or distilled water) oral rinse (swish, gargle, and spit) over 1 minute on day 1. Patients may crossover to arm I on day 2.

Arm II (Placebo-Doxepin)

Total

United States

Region of Enrollment

Robert C. Miller, M.D.

If a patient cancels, is missing baseline data, or only provides baseline data, he/she will be excluded from the statistical analysis. The primary analysis of the total pain reduction will only use primary data from the first phase.

Total Pain Reduction (Mouth and Throat)

If a patient cancels, is missing baseline data, or only provides baseline data, he/she will be excluded from the statistical analysis.

Total Taste of the Oral Rinse

Total Stinging or Burning From the Oral Rinse

Total Drowsiness Increase

At 2 hours after the initial mouthwash

At 4 hours after the initial mouthwash

Incidence of Using Alternative Analgesics Between 2 and 4 Hours After the Initial Mouthwash

Patient Preference for Continuing Therapy With Oral Doxepin Hydrochloride

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Doxepin Hydrochloride in Treating Esophageal Pain in Patients With Thoracic Cancer Receiving Radiation Therapy to the Thorax With or Without Chemotherapy	NCT02062632	Esophageal Carc... Hypopharyngeal ... Laryngeal Carci... Lymphoma Mesothelioma Metastatic Mali... Metastatic Mali... Metastatic Mali... Non-Small Cell ... Sarcoma Small Cell Lung... Thymic Carcinom... Thymoma Thyroid Gland C...	Doxepin Hydroch... Placebo Quality-of-Life... Questionnaire A...	18 Years -	Mayo Clinic
Doxepin Hydrochloride in Treating Oral Mucositis Pain in Patients With Head and Neck Cancer Undergoing Radiation Therapy With or Without Chemotherapy	NCT01156142	Head and Neck C... Mucositis Oral Complicati... Pain	doxepin hydroch... placebo	18 Years -	Alliance for Clinical Trials in Oncology
Doxepin Hydrochloride in Treating Oral Mucositis Pain in Patients With Head and Neck Cancer Undergoing Radiation Therapy With or Without Chemotherapy	NCT01156142	Head and Neck C... Mucositis Oral Complicati... Pain	doxepin hydroch... placebo	18 Years -	Alliance for Clinical Trials in Oncology

Spots Global Cancer Trial Database for doxepin hydrochloride