Malignant Neoplasm, Oral Pain, Stomatitis
Conditions
Brief summary
This phase II trial studies how well methylene blue works in treating patients with cancer and pain associated with oral mucositis. Methylene blue may relieve pain associated with oral mucositis.
Detailed description
PRIMARY OBJECTIVES: I. To evaluate the efficacy of methylene blue (MB) in reducing the severity of mucositis-related pain, measured by numeric rating scale (NRS), in cancer patients who underwent or are undergoing chemotherapy or radiation therapy. OUTLINE: Patients are randomized to 1 of 4 groups. GROUP 1: Patients receive lower dose methylene blue orally (PO) to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. GROUP 2: Patients receive medium dose methylene blue PO to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. GROUP 3: Patients receive higher dose methylene blue PO to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. GROUP 4: Patients receive standard of care therapy. After completion of study treatment, patients are followed up at 1, 2, 7, and 30 days.
Interventions
OTHERBest Practice
Given standard of care therapy
DRUGMethylene Blue
Given lower dose PO
Sponsors
M.D. Anderson Cancer Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients with a cancer diagnosis, receiving chemotherapy, radiation therapy or the combination * Patients with a current diagnosis of oral mucositis * Patients with pain and oral dysfunction associated with oral mucositis despite conventional therapy * Voluntary written consent * Patient must agree to use of contraception or abstinence from sex during the treatment period and for 30 days after patient's last dose
Exclusion criteria
* Patients with known allergy to MB * Patients taking medications with known significant drug interactions * Pregnant or lactating patients * Patients who are cognitively impaired and unable to consent for the study * Patients with risk of broncho-aspiration based on documented swallowing test by a speech pathologist (if available) * Patients with known history of G6PD deficiency * Patients undergoing any other experimental intervention for oral mucositis * Patients who have no pain or impairment in oral function, patients who are not symptomatic * Patients with head and neck cancer * Patients on serotonergic drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool | Baseline up to day 7 | Oral mucositis pain reduction (measured by using the Numeric Rating Scale (NRS); from 0, representing no pain, to 10, representing the worst possible pain) from baseline to 7 days post treatment. The pain scale is included in the Modified Harris mucositis-related pain assessment tool. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Oral Function Burden (OFB) Scores | Baseline up to day 7 | Oral functioning (eat, swallow, talk: unable=2, difficulty=1, able=0. Oral functioning score is the total score of 3 categories, ranged 0-6). Scale is included in the Modified Harris mucositis-related pain assessment tool. Measurements are obtained at day 0, 1, 2, and 7. Modified Harris mucositis-related pain assessment tool. Lowest value=0 representing normal. Highest value =6 representing worst outcome. |
| World Health Organization Oral Mucositis Severity Grades | Up to day 2 | Used the WHO grading system (0= no mucositis, 3=severe mucositis) The clinical severity of the OM was documented only at enrollment point to the study. Most of the patients had the grade 3 mucositis (Soreness/erythema + ulceration + ability to use a liquid diet only), per World Health Organization criteria. See table below which indicates the description of the various grades. Grade Description 0 No changes 1. Soreness/erythema 2. Soreness/erythema + ulceration + ability to eat solid foods 3. Soreness/erythema + ulceration + ability to use a liquid diet only Secondary endpoint included oral functioning burden (0=normal, 6= worse oral function) (OFB; measured on a scale of 0, representing normal, to 6, meaning total inability, reflecting a total score of three categories: the ability to eat, swallow, and talk, each scored as unable = 2, difficult = 1, able = 0). |
| Morphine Equivalent Daily Doses (MEDD) | Baseline to Day 2 | Morphine equivalent daily dose (MEDD) used for oral mucositis pain at 2 post MB administration. Before the study was implemented, it was observed that many patients had pain resolved just within a few doses. Therefore, the study aimed to cover only 100 cc of MB, which typically last about 2 days. Some patients requested more MB after the two days which had to be provided by the pharmacy and ordered by the primary team and paid by patient insurance. This was considered out of the study, but the patients were still followed. Also, there was no average, only self-reported level of pain from the patient at point of data collection. |
| Pain Duration | Up to 30-90 days | Measured the days the patient was in pain. The study aimed to cover only 100 cc of MB, which typically last about 2 days. Some patients requested more MB after the two days which had to be provided by the pharmacy and ordered by the primary team and paid by patient insurance. This was considered out of the study, but the patients were still followed. We followed for 30-90 days (no treatment for 30-90 days), only to observe for AEs. Also, there was no average, only self-reported level of pain from the patient at point of data collection. |
Countries
United States
Participant flow
Recruitment details
Recruitment Period: March 1, 2019, and December 01, 2020- Conducted at The University of Texas MD Anderson Cancer Center.
Pre-assignment details
69 participants signed consent, 9 participants withdrew (3 dropped out of the trial because they were randomized out of the methylene blue group, 5 had progression of disease and could not continue the trial, and 1 was enrolled but withdrew before starting the medication.)
Participants by arm
| Arm | Count |
|---|---|
| Conventional Therapy (Controlled Arm) Participants receive standard of care therapy. | 16 |
| Conventional Therapy + Methylene Blue (MB) 0.025% Participants receive 0.025% dose methylene blue PO to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. | 15 |
| Conventional Therapy + Methylene Blue (MB) 0.05% Participants receive 0.05% dose methylene blue PO to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. | 14 |
| Conventional Therapy + Methylene Blue (MB) 0.1% Participants receive 0.1% dose methylene blue PO to swish and spit for 5 minutes every 6 hours then receive standard of care therapy. | 15 |
| Total | 60 |
Baseline characteristics
| Characteristic | Conventional Therapy (Controlled Arm) | Total | Conventional Therapy + Methylene Blue (MB) 0.1% | Conventional Therapy + Methylene Blue (MB) 0.05% | Conventional Therapy + Methylene Blue (MB) 0.025% |
|---|---|---|---|---|---|
| Age, Continuous | 48 years | 43 years | 32 years | 43 years | 45 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 3 Participants | 1 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 3 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 6 Participants | 2 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) White | 15 Participants | 48 Participants | 11 Participants | 11 Participants | 11 Participants |
| Region of Enrollment United States | 16 participants | 60 participants | 15 participants | 14 participants | 15 participants |
| Sex: Female, Male Female | 6 Participants | 22 Participants | 6 Participants | 5 Participants | 5 Participants |
| Sex: Female, Male Male | 10 Participants | 38 Participants | 9 Participants | 9 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 16 | 1 / 15 | 0 / 14 | 0 / 15 |
| other Total, other adverse events | 0 / 16 | 0 / 15 | 0 / 14 | 0 / 15 |
| serious Total, serious adverse events | 0 / 16 | 0 / 15 | 0 / 14 | 0 / 15 |
Outcome results
Primary
Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool
Oral mucositis pain reduction (measured by using the Numeric Rating Scale (NRS); from 0, representing no pain, to 10, representing the worst possible pain) from baseline to 7 days post treatment. The pain scale is included in the Modified Harris mucositis-related pain assessment tool.
Time frame: Baseline up to day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Therapy (Controlled Arm) | Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool | 1.69 score on a scale | Standard Deviation 3.09 |
| Conventional Therapy + Methylene Blue (MB) 0.025% | Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool | 5.2 score on a scale | Standard Deviation 2.81 |
| Conventional Therapy + Methylene Blue (MB) 0.05% | Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool | 4.54 score on a scale | Standard Deviation 2.93 |
| Conventional Therapy + Methylene Blue (MB) 0.1% | Change in Pain Scores Assessed Within the Numeric Rating Scale (NRS) Component of the Modified Harris Mucositis-related Pain Assessment Tool | 5.15 score on a scale | Standard Deviation 2.64 |
p-value: 0.0034ANOVA
Secondary
Change in Oral Function Burden (OFB) Scores
Oral functioning (eat, swallow, talk: unable=2, difficulty=1, able=0. Oral functioning score is the total score of 3 categories, ranged 0-6). Scale is included in the Modified Harris mucositis-related pain assessment tool. Measurements are obtained at day 0, 1, 2, and 7. Modified Harris mucositis-related pain assessment tool. Lowest value=0 representing normal. Highest value =6 representing worst outcome.
Time frame: Baseline up to day 7
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Conventional Therapy (Controlled Arm) | Change in Oral Function Burden (OFB) Scores | 0.81 score on a scale | Standard Deviation 1.11 |
| Conventional Therapy + Methylene Blue (MB) 0.025% | Change in Oral Function Burden (OFB) Scores | 2.47 score on a scale | Standard Deviation 1.55 |
| Conventional Therapy + Methylene Blue (MB) 0.05% | Change in Oral Function Burden (OFB) Scores | 2.79 score on a scale | Standard Deviation 1.72 |
| Conventional Therapy + Methylene Blue (MB) 0.1% | Change in Oral Function Burden (OFB) Scores | 2.87 score on a scale | Standard Deviation 1.6 |
p-value: 0.0008ANOVA
Secondary
Morphine Equivalent Daily Doses (MEDD)
Morphine equivalent daily dose (MEDD) used for oral mucositis pain at 2 post MB administration. Before the study was implemented, it was observed that many patients had pain resolved just within a few doses. Therefore, the study aimed to cover only 100 cc of MB, which typically last about 2 days. Some patients requested more MB after the two days which had to be provided by the pharmacy and ordered by the primary team and paid by patient insurance. This was considered out of the study, but the patients were still followed. Also, there was no average, only self-reported level of pain from the patient at point of data collection.
Time frame: Baseline to Day 2
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Therapy (Controlled Arm) | Morphine Equivalent Daily Doses (MEDD) | 117.5 mg |
| Conventional Therapy + Methylene Blue (MB) 0.025% | Morphine Equivalent Daily Doses (MEDD) | 115 mg |
| Conventional Therapy + Methylene Blue (MB) 0.05% | Morphine Equivalent Daily Doses (MEDD) | 107 mg |
| Conventional Therapy + Methylene Blue (MB) 0.1% | Morphine Equivalent Daily Doses (MEDD) | 120 mg |
p-value: 0.9182Fisher Exact
Secondary
Pain Duration
Measured the days the patient was in pain. The study aimed to cover only 100 cc of MB, which typically last about 2 days. Some patients requested more MB after the two days which had to be provided by the pharmacy and ordered by the primary team and paid by patient insurance. This was considered out of the study, but the patients were still followed. We followed for 30-90 days (no treatment for 30-90 days), only to observe for AEs. Also, there was no average, only self-reported level of pain from the patient at point of data collection.
Time frame: Up to 30-90 days
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Conventional Therapy (Controlled Arm) | Pain Duration | 5.5 days |
| Conventional Therapy + Methylene Blue (MB) 0.025% | Pain Duration | 8 days |
| Conventional Therapy + Methylene Blue (MB) 0.05% | Pain Duration | 6 days |
| Conventional Therapy + Methylene Blue (MB) 0.1% | Pain Duration | 5 days |
p-value: 0.1046Fisher Exact
Secondary
World Health Organization Oral Mucositis Severity Grades
Used the WHO grading system (0= no mucositis, 3=severe mucositis) The clinical severity of the OM was documented only at enrollment point to the study. Most of the patients had the grade 3 mucositis (Soreness/erythema + ulceration + ability to use a liquid diet only), per World Health Organization criteria. See table below which indicates the description of the various grades. Grade Description 0 No changes 1. Soreness/erythema 2. Soreness/erythema + ulceration + ability to eat solid foods 3. Soreness/erythema + ulceration + ability to use a liquid diet only Secondary endpoint included oral functioning burden (0=normal, 6= worse oral function) (OFB; measured on a scale of 0, representing normal, to 6, meaning total inability, reflecting a total score of three categories: the ability to eat, swallow, and talk, each scored as unable = 2, difficult = 1, able = 0).
Time frame: Up to day 2
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Conventional Therapy (Controlled Arm) | World Health Organization Oral Mucositis Severity Grades | Grade 2 | 1 Participants |
| Conventional Therapy (Controlled Arm) | World Health Organization Oral Mucositis Severity Grades | Grade 3 | 15 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.025% | World Health Organization Oral Mucositis Severity Grades | Grade 3 | 15 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.025% | World Health Organization Oral Mucositis Severity Grades | Grade 2 | 0 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.05% | World Health Organization Oral Mucositis Severity Grades | Grade 2 | 1 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.05% | World Health Organization Oral Mucositis Severity Grades | Grade 3 | 13 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.1% | World Health Organization Oral Mucositis Severity Grades | Grade 2 | 4 Participants |
| Conventional Therapy + Methylene Blue (MB) 0.1% | World Health Organization Oral Mucositis Severity Grades | Grade 3 | 11 Participants |