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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:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Alliance for Clinical Trials in Oncology

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Supportive Care
Conditions Head and Neck Cancer
Mucositis
Oral Complications of Radiation Therapy
Pain
Interventions Drug: doxepin hydrochloride
Other: placebo
Enrollment 155
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description 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. 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.
Period Title: Overall Study
Started 77 78
Completed 69 71
Not Completed 8 7
Reason Not Completed
Withdrawal by Subject             8             6
Ineligible             0             1
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin) Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 69 71 140
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Full Range)
Unit of measure:  Years
Number Analyzed 69 participants 71 participants 140 participants
62
(39.0 to 93.0)
60
(37.0 to 86.0)
61
(37.0 to 93.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 69 participants 71 participants 140 participants
Female
13
  18.8%
15
  21.1%
28
  20.0%
Male
56
  81.2%
56
  78.9%
112
  80.0%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 69 participants 71 participants 140 participants
69 71 140
1.Primary Outcome
Title Total Pain Reduction (Mouth and Throat)
Hide Description 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.
Time Frame Baseline and Day 1
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Mean (Standard Deviation)
Unit of Measure: units on a scale
-9.1  (7.9) -4.7  (6.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -4.4
Confidence Interval (2-Sided) 95%
-6.7 to -2.1
Estimation Comments [Not Specified]
2.Secondary Outcome
Title Total Taste of the Oral Rinse
Hide Description 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.
Time Frame Up to 9 days
Hide Outcome Measure Data
Hide Analysis Population Description
If a patient cancels, is missing baseline data, or only provides baseline data, he/she will be excluded from the statistical analysis.
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Mean (Standard Deviation)
Unit of Measure: units on a scale
7.7  (7.1) 5.1  (7.7)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0018
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.6
Confidence Interval (2-Sided) 95%
0.1 to 5.1
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Total Stinging or Burning From the Oral Rinse
Hide Description 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.
Time Frame Up to 9 days
Hide Outcome Measure Data
Hide Analysis Population Description
If a patient cancels, is missing baseline data, or only provides baseline data, he/she will be excluded from the statistical analysis.
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Mean (Standard Deviation)
Unit of Measure: units on a scale
9.6  (8.4) 4.0  (8.0)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.001
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 5.6
Confidence Interval (2-Sided) 95%
2.9 to 8.3
Estimation Comments [Not Specified]
4.Secondary Outcome
Title Total Drowsiness Increase
Hide Description 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.
Time Frame Up to 9 days
Hide Outcome Measure Data
Hide Analysis Population Description
If a patient cancels, is missing baseline data, or only provides baseline data, he/she will be excluded from the statistical analysis.
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Mean (Standard Deviation)
Unit of Measure: units on a scale
-0.7  (10.3) -2.4  (6.6)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0297
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.7
Confidence Interval (2-Sided) 95%
-1.2 to 4.6
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Incidence of Using Alternative Analgesics Between 2 and 4 Hours After the Initial Mouthwash
Hide Description 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 .
Time Frame Up to 9 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Measure Type: Number
Unit of Measure: percentage of patients
At 2 hours after the initial mouthwash 8.8 2.9
At 4 hours after the initial mouthwash 16.9 14.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments At 2 hours after initial mouthwash
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1392
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Show Statistical Analysis 2 Hide Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments At 4 hours after initial mouthwash
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6989
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
6.Secondary Outcome
Title Patient Preference for Continuing Therapy With Oral Doxepin Hydrochloride
Hide Description 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.
Time Frame Up to 9 days
Hide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 69 71
Measure Type: Number
Unit of Measure: percentage of patients
77.3 51.5
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Arm I (Doxepin-Placebo), Arm II (Placebo-Doxepin)
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0018
Comments [Not Specified]
Method Chi-squared
Comments [Not Specified]
Time Frame Adverse events are assessed during the Active Monitoring Phase at the following time points: at time Dose 1 of study treatment is administered, at time of Dose 2 crossover, during the Optional Continuation Phase, and at the end of the study. All adverse events are collected during the first day; up to 9 days.
Adverse Event Reporting Description 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.
 
Arm/Group Title Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/74 (0.00%)      0/75 (0.00%)    
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Arm I (Doxepin-Placebo) Arm II (Placebo-Doxepin)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   10/74 (13.51%)      8/75 (10.67%)    
Gastrointestinal disorders     
Diarrhea  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Dry mouth  1  3/74 (4.05%)  4 0/75 (0.00%)  0
Dysphagia  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Mucositis oral  1  4/74 (5.41%)  9 6/75 (8.00%)  12
Nausea  1  1/74 (1.35%)  1 1/75 (1.33%)  2
Oral pain  1  2/74 (2.70%)  5 2/75 (2.67%)  2
Salivary duct inflammation  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Vomiting  1  0/74 (0.00%)  0 1/75 (1.33%)  2
General disorders     
Fatigue  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Metabolism and nutrition disorders     
Anorexia  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Dehydration  1  0/74 (0.00%)  0 1/75 (1.33%)  2
Nervous system disorders     
Lethargy  1  0/74 (0.00%)  0 1/75 (1.33%)  1
Somnolence  1  1/74 (1.35%)  1 2/75 (2.67%)  2
Respiratory, thoracic and mediastinal disorders     
Cough  1  1/74 (1.35%)  1 0/75 (0.00%)  0
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 9
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Robert C. Miller, M.D.
Organization: Mayo Clinic
Phone: 507/266-6247
EMail: Miller.Robert@mayo.edu
Layout table for additonal information
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 Submitted: July 1, 2010
First Posted: July 2, 2010
Results First Submitted: December 12, 2016
Results First Posted: May 8, 2017
Last Update Posted: August 9, 2017