Manuka Honey in Preventing Esophagitis-Related Pain in Patients Receiving Chemotherapy and Radiation Therapy For Lung Cancer

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT01262560
• Collaborator: National Cancer Institute (NCI) (NIH), NRG Oncology (Other)
• Enrollment: 163
• Locations: 59
• Arms: 3
• Duration (Months): 33
• Patients Per Site: 2.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

RATIONALE: Manuka honey may prevent or reduce esophagitis-related pain caused by chemotherapy and radiation therapy. It is not yet known whether Manuka honey is more effective than standard care in preventing pain.

PURPOSE: This randomized phase II clinical trial is studying Manuka honey to see how well it works in preventing esophagitis-related pain in patients receiving chemotherapy and radiation therapy for lung cancer.

Condition or Disease	Intervention/Treatment	Phase
Dysphagia; Lung Cancer; Pain; Esophagitis	Drug: Manuka honey in liquid form; Drug: Manuka honey in lozenge form; Drug: Standard supportive care	Phase 2

Detailed Description

OBJECTIVES:

Primary

• Evaluate the relative efficacy of 4 times a day consumption of liquid or lozenge Manuka honey to delay or prevent radiation esophagitis-related pain (during combined chemotherapy and radiation therapy for lung cancer) as compared to standard supportive treatment, as measured at week 4 by Numerical Rating Pain Scale (NRPS) for pain upon swallowing.

Secondary

• Evaluate the trend of severity of radiation esophagitis-related pain during combined chemotherapy and radiation therapy for lung cancer using weekly measurements of the NRPS.

• Evaluate the adverse events associated with Manuka honey, as measured by CTCAE, v. 4.

• Evaluate the severity of radiation esophagitis (grade 3-4, CTCAE, v. 4).

• Assess weight loss (percent weight change from baseline to 4 weeks).

• Assess quality of life (QOL) and pain, as measured by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ-30) global QOL score and pain symptom subscale.

• Assess patient-reported dysphagia via a daily patient log.

• Assess nutritional status, as measured by the mean change in serum prealbumin levels from baseline to 4 weeks.

• Assess opioid use by collecting the patient's narcotic use in the previous 24-hour period at each weekly evaluation.

• Evaluate patient-reported adverse events associated with Manuka honey using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).

OUTLINE: This is a multicenter study. Patients are stratified according to the percentage of esophagus in the radiation field (V60 < 30% vs V60 ≥ 30%). Patients are randomized to 1 of 3 treatment arms.

• Arm I: Patients receive standard supportive care for esophagitis-related pain as needed during chemoradiotherapy.

• Arm II: Patients swallow liquid Manuka honey slowly over 3-5 minutes. Patients must refrain from eating and drinking for 1 hour after administration. Treatment continues 4 times per day during chemoradiotherapy.

• Arm III: Patients place Manuka honey lozenges in their mouth one at a time and swallow the honey as it dissolves (no chewing or swallowing it whole). Patients must refrain from eating and drinking for 1 hour after administration. Treatment continues 4 times per day during chemoradiotherapy.

Patients complete quality of life, pain swallowing diary, and pain assessments (Numerical Rating Pain Scale, EORTC QLQ-30 and Pain Subscale, and PRO-CTCAE) periodically during study treatment.

Patients are followed up at 12 weeks from the start of study treatment.

Study Design

• Study Type: Interventional
• Actual Enrollment: 163 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: Phase II Randomized Trial of Prophylactic Manuka Honey for the Reduction of Chemoradiation Therapy Induced Esophagitis-Related Pain During the Treatment of Lung Cancer
• Study Start Date: Feb 1, 2012
• Actual Primary Completion Date: Feb 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Supportive Care Standard supportive care	Drug: Standard supportive care; Patients receive standard supporting care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment. The following regimen is recommended, but the local standard of care is permitted. A compound containing viscous lidocaine and magnesium aluminum oxide (Maalox®); Liquid or solid oxycodone, 5-10 mg, every 3 hours as needed.
Experimental: Liquid Manuka Honey Manuka honey in liquid form	Drug: Manuka honey in liquid form; Patients swallow 10 cc (approximately 2 level teaspoons) of liquid Manuka honey 4 times per day while awake over an approximately 12 hour period (e.g. 8 a.m., Noon, 4 p.m., and 8 p.m.) 7 days/week during concurrent chemotherapy and radiation treatment.
Experimental: Lozenge Manuka Honey Manuka honey in lozenge form	Drug: Manuka honey in lozenge form; Patients place 2 lozenges (the equivalent of 10 cc of liquid Manuka honey), one at a time, in the mouth, allowing each lozenge to dissolve on the tongue/in the mouth, swallowing the honey as it dissolves. Patients do this 4 times per day while awake over an approximately 12 hour period (e.g. 8 a.m., Noon, 4 p.m., and 8 p.m.) 7 days/week during concurrent chemotherapy and radiation treatment.

Outcome Measures

Primary Outcome Measures

1. Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS) [Baseline and 4 weeks from the start of treatment]

   Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from the 4-week value. The experimental arms (honey) were compared to the standard arm (supportive care).

Secondary Outcome Measures

1. Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS) [Baseline, weekly during treatment, and 12 weeks from the start of treatment]

   Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from values at the later time points. The experimental arms (honey) were compared to the standard arm (supportive care).

2. Dysphagia Via Daily Patient Log [Weekly during treatment and 12 weeks from the start of treatment]

   Dysphagia, as reported by the patient, was measured by the patient swallowing diary. Swallowing score has increasing severity 1-5, where 1 = "none" and 5 = "cannot swallow liquids".

3. Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks [Baseline, 4 and 12 weeks from the start of treatment]

   The pain symptom subscale (2 items) evaluated pain and the global score (30 items) evaluated quality of life. Each ranges from 0-100 with lower scores indicating lesser burden and improved symptoms or quality of life.

4. Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4) [Up to 12 weeks from the start of treatment]

   Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. For esophagitis specifically, Grade 3 criteria includes severely altered eating/swallowing, tube feeding, total parenteral nutrition (TPN) or hospitalization indicated. Grade 4 criteria include life-threatening consequences, urgent operative intervention indicated.

5. Percent Change in Weight From Baseline to 4 Weeks [Baseline and 4 weeks from the start of treatment]

6. Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks) [Baseline and 4 weeks from the start of treatment]

7. Percentage of Patients Using Opioids [Baseline, 4 weeks, end of radiation treatment, and 12 weeks from the start of treatment]

   The percentage of patients using opioid analgesics is reported. Use of opioid analgesics was assessed for a 24-hour period before completing the assessment. Patients with at least one reported administration of opioid analgesic were considered to have received opioid analgesics.

8. Adverse Events Associated With Manuka Honey Using CTCAE v4.0 [Until 12 weeks from the start of treatment]

   Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.

9. Patient Reported Difficulty in Swallowing Associated With Manuka Honey Using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) [Baseline and 4 weeks from the start of treatment]

   Change from baseline to four weeks in patient-reported difficulty in swallowing via the PRO-CTCAE. PRO-CTCAE is an item bank consisting of individual items to assess adverse symptom events from the patient perspective. There are 78 symptoms included in the survey but the primary item of interest assesses difficulty swallowing. For each AE in the PRO-CTCAE, between 1 and 3 items are included to assess the frequency, severity, and/or interference with activities related to that AE. Frequency questions have responses ranging from never, which is scored as a 0, to almost constantly, which is scored as a 4. Severity questions have responses ranging from none, which is scored as a 0, to very severe, which is scored as a 4. Interference questions have responses ranging from not at all, which is scored as a 0, to very much, which is scored as a 4. Difficulty in swallowing only has a severity question.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

DISEASE CHARACTERISTICS:

• Patients being treated with combination chemotherapy (definitive or adjuvant) and radiation therapy once daily for small cell or non-small cell lung cancer (primary population for the trial)

• Patients can receive chemoradiotherapy while on a Radiation Therapy Oncology Group (RTOG) lung trial or while not being on a clinical trial

• No patients receiving chemoradiotherapy while enrolled on a single institution trial or trials coordinated by other cooperative groups

• No patients with metastatic disease

• At least 5 cm of the esophagus must be in the 60 Gy isodose volume in 1.6 to 2.0 Gy fractions

PATIENT CHARACTERISTICS:

• Age 18 and up

• Able to swallow thick liquids prior to treatment

• Able to speak English or Spanish in order to complete required forms (verbal completion is adequate)

• No patients with poorly controlled diabetes

• No known hypersensitivity to honey

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics

• No patients who have received prior chemotherapy or radiation therapy

• No patients receiving more than once daily treatments

• Therapeutic use of honey other than the Manuka honey provided for this trial is not allowed while patients are on study

• Patients must also avoid honey-flavored medical products and/or sugary, viscous substances

• Amifostine is not permitted

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Providence Cancer Center at Providence Hospital	Mobile	Alabama	United States	36608
2	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California	United States	94115
3	Stanford Cancer Center	Stanford	California	United States	94305-5824
4	CCOP - Christiana Care Health Services	Newark	Delaware	United States	19713
5	Baptist Cancer Institute - Jacksonville	Jacksonville	Florida	United States	32207
6	CCOP - Mount Sinai Medical Center	Miami Beach	Florida	United States	33140
7	Florida Cancer Center - Palatka	Palatka	Florida	United States	32177
8	Piedmont Fayette Hospital	Fayetteville	Georgia	United States	30214
9	Nancy N. and J. C. Lewis Cancer and Research Pavilion at St. Joseph's/Candler	Savannah	Georgia	United States	31405
10	Queen's Cancer Institute at Queen's Medical Center	Honolulu	Hawaii	United States	96813
11	Hawaii Medical Center - East	Honolulu	Hawaii	United States	96817
12	OSF St. Francis Medical Center	Peoria	Illinois	United States	61615-7827
13	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
14	Parkview Regional Cancer Center at Parkview Health	Fort Wayne	Indiana	United States	46805
15	Cancer Center at Ball Memorial Hospital	Muncie	Indiana	United States	47303-3499
16	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
17	Cape Cod Hospital	Hyannis	Massachusetts	United States	02601
18	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
19	Regional Cancer Center at Singing River Hospital	Pascagoula	Mississippi	United States	39581
20	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
21	David C. Pratt Cancer Center at St. John's Mercy	Saint Louis	Missouri	United States	63141
22	Payson Center for Cancer Care at Concord Hospital	Concord	New Hampshire	United States	03301
23	Seacoast Cancer Center at Wentworth - Douglass Hospital	Dover	New Hampshire	United States	03820
24	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
25	Elliot Regional Cancer Center at Elliot Hospital	Manchester	New Hampshire	United States	03103
26	Monmouth Medical Center	Long Branch	New Jersey	United States	07740-6395
27	Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton	Marlton	New Jersey	United States	08053
28	CCOP - Hematology-Oncology Associates of Central New York	East Syracuse	New York	United States	13057
29	Highland Hospital of Rochester	Rochester	New York	United States	14620
30	James P. Wilmot Cancer Center at University of Rochester Medical Center	Rochester	New York	United States	14642
31	Presbyterian Cancer Center at Presbyterian Hospital	Charlotte	North Carolina	United States	28233-3549
32	Duke Cancer Institute	Durham	North Carolina	United States	27710
33	Pardee Memorial Hospital	Hendersonville	North Carolina	United States	28791
34	FirstHealth Moore Regional Community Hospital Comprehensive Cancer Center	Pinehurst	North Carolina	United States	28374
35	Rex Cancer Center at Rex Hospital	Raleigh	North Carolina	United States	27607
36	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096
37	Trinity CancerCare Center	Minot	North Dakota	United States	58701
38	Mercy Cancer Center at Mercy Medical Center	Canton	Ohio	United States	44708
39	Case Comprehensive Cancer Center	Cleveland	Ohio	United States	44106-5065
40	Cleveland Clinic Cancer Center at Fairview Hospital	Cleveland	Ohio	United States	44111
41	Cleveland Clinic Taussig Cancer Center	Cleveland	Ohio	United States	44195
42	Cleveland Clinic Cancer Center	Independence	Ohio	United States	44131
43	Hillcrest Cancer Center at Hillcrest Hospital	Mayfield Heights	Ohio	United States	44124
44	Parma Community General Hospital	Parma	Ohio	United States	44129
45	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
46	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
47	Geisinger Cancer Institute at Geisinger Health	Danville	Pennsylvania	United States	17822-0001
48	Northeast Radiation Oncology Center	Dunmore	Pennsylvania	United States	18512
49	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
50	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
51	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301-1792
52	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
53	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
54	Gibbs Regional Cancer Center at Spartanburg Regional Medical Center	Spartanburg	South Carolina	United States	29303
55	University of Texas Medical Branch	Galveston	Texas	United States	77555-0361
56	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229-3900
57	St. Joseph Cancer Center	Bellingham	Washington	United States	98225
58	St. Mary's Hospital Medical Center - Green Bay	Green Bay	Wisconsin	United States	54303
59	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)
• NRG Oncology

Investigators

• Principal Investigator: Lawrence B. Berk, MD, PhD, Tampa General Hospital, University of South Florida

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT01262560
• Other Study ID Numbers: RTOG 1012; RTOG-1012; CDR0000690182; NCI-2011-02620
• First Posted: Dec 17, 2010
• Last Update Posted: Aug 31, 2017
• Last Verified: Aug 1, 2017

• Keywords provided by Radiation Therapy Oncology Group: pain; dysphagia; recurrent non-small cell lung cancer; stage IA non-small cell lung cancer; stage IB non-small cell lung cancer; stage IIA non-small cell lung cancer; stage IIB non-small cell lung cancer; stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer; extensive stage small cell lung cancer; limited stage small cell lung cancer; recurrent small cell lung cancer; esophagitis
• Additional relevant MeSH terms: Lung Neoplasms; Deglutition Disorders; Esophagitis

Study Results

Participant Flow

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Period Title: Overall Study
STARTED	53	54	56
COMPLETED	53	53	54
NOT COMPLETED	0	1	2

Baseline Characteristics

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey	Total
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.	Total of all reporting groups
Overall Participants	53	53	54	160
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	65	66	65	65
Sex: Female, Male (Count of Participants)
Female	27 50.9%	24 45.3%	23 42.6%	74 46.3%
Male	26 49.1%	29 54.7%	31 57.4%	86 53.8%

Outcome Measures

1. Primary Outcome

Title	Change in Radiation Esophagitis-related Pain at 4 Weeks as Measured by the Numerical Rating Pain Scale for Pain on Swallowing (NRPS)
Description	Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from the 4-week value. The experimental arms (honey) were compared to the standard arm (supportive care).
Time Frame	Baseline and 4 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients with NRPS score at both baseline and 4 weeks.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	40	41	38
Median (Inter-Quartile Range) [units on a scale]	1	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey
	Comments	Null hypothesis: Manuka honey in liquid form is/not effective at reducing esophagitis-related pain, measured by mean change score from 0 to 4 weeks. A 2-sample t-test for difference of means with alpha 0.05 after adjusting for multiple comparisons (1-sided with overall alpha 0.1 before the Bonferroni adjustment) and 80% statistical power for each hypothesis test requires 45 patients per arm to detect >= 15% relative reduction (absolute difference of mean change score of 3.1; effect size=0.53).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.92
	Comments	Due to the skewed nature of the data, median was reported instead of mean.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Each arm had less than the designed sample size. Therefore the statistical power was reduced (76% instead of 80%).

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Lozenge Manuka Honey
	Comments	Null hypothesis: Manuka honey in lozenge form is/not effective at reducing esophagitis-related pain, measured by mean change score from 0 to 4 weeks. A 2-sample t-test for difference of means with alpha 0.05 after adjusting for multiple comparisons (1-sided with overall alpha 0.1 before the Bonferroni adjustment) and 80% statistical power for each hypothesis test requires 45 patients per arm to detect >= 15% relative reduction (absolute difference of mean change score of 3.1; effect size=0.53).
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.93
	Comments	Due to the skewed nature of the data, median was reported instead of mean.
	Method	Wilcoxon (Mann-Whitney)
	Comments	Each arm had less than the designed sample size. Therefore the statistical power was reduced (76% instead of 80%)

2. Secondary Outcome

Title	Radiation Esophagitis-related Pain During Treatment as Measured During Treatment and 12 Weeks by the Numerical Rating Pain Scale (NRPS)
Description	Esophagitis-related pain was measured using patient-reported pain on swallowing as assessed by the Numerical Rating Pain Scale (NRPS), an 11-point scale (0-10) in which 0 indicates no pain and 10 indicates the worst pain imaginable. Generally, scores of 1-4 indicate mild pain, scores of 5-6 indicate moderate pain, and scores of 7-10 indicate severe pain. Change was calculated by subtracting the baseline value from values at the later time points. The experimental arms (honey) were compared to the standard arm (supportive care).
Time Frame	Baseline, weekly during treatment, and 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Eligible patients who started protocol treatment with at least 1 NRPS score completed across all time points

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	49	50	51
Baseline	0	0	0
Week 1	0	0	0
Week 2	0	0	0
Week 3	0	1	1
4 weeks	1	1	2
Week 5	2.5	2	3
End of RT	3	3	4
Week 12	0	0	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.87
	Comments
	Method	Mixed Models Analysis
	Comments	Explanatory variables are reported separately.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.46
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0023
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0025
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with NRPS score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	Each explanatory variable is reported separately.
	Method	Mixed Models Analysis
	Comments

3. Secondary Outcome

Title	Dysphagia Via Daily Patient Log
Description	Dysphagia, as reported by the patient, was measured by the patient swallowing diary. Swallowing score has increasing severity 1-5, where 1 = "none" and 5 = "cannot swallow liquids".
Time Frame	Weekly during treatment and 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients who received protocol treatment with at least one dysphagia score completed across all time points.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	46	50	59
Baseline	1	1	1
Week 1	1	1	1
Week 2	1	1	1.07
Week 3	1.36	2	1.86
Week 4	1.86	2	2.07
Week 5	2.5	2	2.71
End of RT	2	2.86	3
Week 12	1	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. Treatment (Liquid Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.70
	Comments
	Method	Mixed Models Analysis
	Comments	Explanatory variables are reported separately.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.71
	Comments
	Method	Mixed Models Analysis
	Comments	Explanatory variables are reported separately.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0051
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with dysphagia score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

4. Secondary Outcome

Title	Quality of Life and Pain, as Measured by the EORTC QLQ-30 Global QOL Score and Pain Symptom Subscale at 4 and 12 Weeks
Description	The pain symptom subscale (2 items) evaluated pain and the global score (30 items) evaluated quality of life. Each ranges from 0-100 with lower scores indicating lesser burden and improved symptoms or quality of life.
Time Frame	Baseline, 4 and 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients who received protocol treatment with at least 1 EORTC score completed across all time points.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	48	50	52
Baseline - Global health status	66.67	66.67	66.67
Baseline - Pain	16.67	16.67	16.67
Week 4 - Global health status	66.67	62.50	66.67
Week 4 - Pain	25.00	16.67	33.33
Week 12 - Global health status	66.67	58.33	66.67
Week 12 - Pain	0.00	16.67	16.67

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.086
	Comments
	Method	Mixed Models Analysis
	Comments	Explanatory variables are reported separately.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.44
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0066
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC global health status (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.36
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Liquid Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.94
	Comments
	Method	Mixed Models Analysis
	Comments	Explanatory variables are reported separately.

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Treatment (Lozenge Honey vs. Supportive Care) is reported here.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.58
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Percentage of esophagus is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Opioid use is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Mixed Models Analysis
	Comments	Each exploratory variable is reported separately.

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey, Lozenge Manuka Honey
	Comments	A linear fixed effects model using maximum likelihood estimation was run with EORTC pain score (baseline, weekly during treatment and 12 weeks from the end of treatment) as the outcome of interest. Percentage of esophagus (V60>=30% as reference level), opioid use ("yes" as reference level), time, and treatment arm were factors in the model. The results for each explanatory variable are reported separately. Time is reported here.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	Mixed Models Analysis
	Comments	Each explanatory variable is reported separately.

5. Secondary Outcome

Title	Percentage of Participants With Radiation Esophagitis Grade 3-4 (CTCAE v. 4)
Description	Adverse events are graded using CTCAE v3.0. Grade refers to the severity of the AE. The CTCAE v3.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE. For esophagitis specifically, Grade 3 criteria includes severely altered eating/swallowing, tube feeding, total parenteral nutrition (TPN) or hospitalization indicated. Grade 4 criteria include life-threatening consequences, urgent operative intervention indicated.
Time Frame	Up to 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients who started protocol treatment

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	48	50	50
Number (95% Confidence Interval) [percentage of participants]	12.5 23.6%	2.0 3.8%	6.0 11.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.06
	Comments	Significance level = 0.05
	Method	Fisher Exact
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Lozenge Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.31
	Comments	Significance level = 0.05
	Method	Fisher Exact
	Comments

6. Secondary Outcome

Title	Percent Change in Weight From Baseline to 4 Weeks
Time Frame	Baseline and 4 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients with weight at both baseline and 4 weeks.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	50	51	51
Mean (95% Confidence Interval) [percentage of baseline value]	-2.22	-0.62	-2.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.53
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Lozenge Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

7. Secondary Outcome

Title	Nutritional Status (Change in Serum Prealbumin Levels From Baseline to 4 Weeks)
Time Frame	Baseline and 4 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients with serum prealbumin at baseline and 4 weeks.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	50	51	51
Mean (95% Confidence Interval) [mg/dl]	-3.34	5.25	0.17

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.20
	Comments
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Lozenge Manuka Honey
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.28
	Comments
	Method	t-test, 2 sided
	Comments

8. Secondary Outcome

Title	Percentage of Patients Using Opioids
Description	The percentage of patients using opioid analgesics is reported. Use of opioid analgesics was assessed for a 24-hour period before completing the assessment. Patients with at least one reported administration of opioid analgesic were considered to have received opioid analgesics.
Time Frame	Baseline, 4 weeks, end of radiation treatment, and 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients with opioid use information at at least one time point.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	53	53	54
Baseline	13.2 24.9%	9.4 17.7%	13.0 24.1%
Week 4	37.0 69.8%	14.3 27%	29.2 54.1%
End of RT	46.5 87.7%	36.2 68.3%	43.2 80%
Week 12	32.6 61.5%	17.4 32.8%	18.2 33.7%

9. Secondary Outcome

Title	Adverse Events Associated With Manuka Honey Using CTCAE v4.0
Description	Adverse events are graded using CTCAE v4.0. Grade refers to the severity of the AE. The CTCAE v4.0 assigns Grades 1 through 5 with unique clinical descriptions of severity for each AE based on this general guideline: Grade 1 Mild AE, Grade 2 Moderate AE, Grade 3 Severe AE, Grade 4 Life-threatening or disabling AE, Grade 5 Death related to AE.
Time Frame	Until 12 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients who started protocol treatment.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	48	50	50
Grade 1	6.3	16.0	12.0
Grade 2	20.8	26.0	18.0
Grade 3	10.4	8.0	8.0
Grade 4	2.1	0.0	2.0
Grade 5	0.0	0.0	0.0

10. Secondary Outcome

Title	Patient Reported Difficulty in Swallowing Associated With Manuka Honey Using the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE)
Description	Change from baseline to four weeks in patient-reported difficulty in swallowing via the PRO-CTCAE. PRO-CTCAE is an item bank consisting of individual items to assess adverse symptom events from the patient perspective. There are 78 symptoms included in the survey but the primary item of interest assesses difficulty swallowing. For each AE in the PRO-CTCAE, between 1 and 3 items are included to assess the frequency, severity, and/or interference with activities related to that AE. Frequency questions have responses ranging from never, which is scored as a 0, to almost constantly, which is scored as a 4. Severity questions have responses ranging from none, which is scored as a 0, to very severe, which is scored as a 4. Interference questions have responses ranging from not at all, which is scored as a 0, to very much, which is scored as a 4. Difficulty in swallowing only has a severity question.
Time Frame	Baseline and 4 weeks from the start of treatment

Outcome Measure Data

Analysis Population Description

Randomized eligible patients who started treatment with measure at both baseline and 4 weeks.

Arm/Group Title	Supportive Care	Liquid Manuka Honey	Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.	Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.	Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
Measure Participants	36	33	35
Median (Inter-Quartile Range) [units on a scale]	1	1	1

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Liquid Manuka Honey
	Comments	Each experimental arm was compared to the control arm (i.e. 2 comparisons) using two-sample t-tests. Forty-five patients with data in each arm, provides 80% power to detect an effect size (in standard deviation units) of 0.60 and 90% power to detect an effect size of 0.69 using a two-sided T-test with a Bonferroni adjusted significance level of 0.05 for each comparison (overall alpha 0.10). Due to the lack of prior data on the PRO-CTCAE, moderate effect sizes were used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.39
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Because data was not normally distributed, this test was used instead of the t-test.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Supportive Care, Lozenge Manuka Honey
	Comments	Each experimental arm was compared to the control arm (i.e. 2 comparisons) using two-sample t-tests. Forty-five patients with data in each arm, provides 80% power to detect an effect size (in standard deviation units) of 0.60 and 90% power to detect an effect size of 0.69 using a two-sided T-test with a Bonferroni adjusted significance level of 0.05 for each comparison (overall alpha 0.10). Due to the lack of prior data on the PRO-CTCAE, moderate effect sizes were used.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.69
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments	Because data was not normally distributed, this test was used instead of the t-test.

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Supportive Care		Liquid Manuka Honey		Lozenge Manuka Honey
Arm/Group Description	Standard supportive care for esophagitis-related pain as needed during concurrent chemotherapy and radiation treatment.		Manuka honey in liquid form during concurrent chemotherapy and radiation treatment.		Manuka honey in lozenge form during concurrent chemotherapy and radiation treatment.
All Cause Mortality
	Supportive Care		Liquid Manuka Honey		Lozenge Manuka Honey
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Supportive Care		Liquid Manuka Honey		Lozenge Manuka Honey
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/48 (33.3%)		13/50 (26%)		9/50 (18%)
Blood and lymphatic system disorders
Anemia	0/48 (0%)		2/50 (4%)		0/50 (0%)
Febrile neutropenia	1/48 (2.1%)		1/50 (2%)		3/50 (6%)
Cardiac disorders
Atrial fibrillation	1/48 (2.1%)		0/50 (0%)		1/50 (2%)
Cardiac arrest	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Myocardial infarction	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Gastrointestinal disorders
Abdominal pain	0/48 (0%)		0/50 (0%)		1/50 (2%)
Colonic perforation	0/48 (0%)		0/50 (0%)		1/50 (2%)
Diarrhea	0/48 (0%)		1/50 (2%)		0/50 (0%)
Dysphagia	0/48 (0%)		1/50 (2%)		0/50 (0%)
Esophagitis	5/48 (10.4%)		1/50 (2%)		2/50 (4%)
Gastrointestinal disorders - Other	0/48 (0%)		0/50 (0%)		1/50 (2%)
Nausea	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Small intestinal obstruction	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Vomiting	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
General disorders
Fatigue	0/48 (0%)		1/50 (2%)		0/50 (0%)
Infusion related reaction	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Infections and infestations
Lung infection	2/48 (4.2%)		0/50 (0%)		2/50 (4%)
Sepsis	1/48 (2.1%)		0/50 (0%)		1/50 (2%)
Skin infection	0/48 (0%)		1/50 (2%)		0/50 (0%)
Urinary tract infection	1/48 (2.1%)		2/50 (4%)		0/50 (0%)
Investigations
Aspartate aminotransferase increased	0/48 (0%)		0/50 (0%)		1/50 (2%)
Neutrophil count decreased	1/48 (2.1%)		2/50 (4%)		2/50 (4%)
Platelet count decreased	1/48 (2.1%)		2/50 (4%)		1/50 (2%)
Weight loss	0/48 (0%)		1/50 (2%)		0/50 (0%)
White blood cell decreased	1/48 (2.1%)		2/50 (4%)		2/50 (4%)
Metabolism and nutrition disorders
Anorexia	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Dehydration	3/48 (6.3%)		2/50 (4%)		1/50 (2%)
Hyperglycemia	0/48 (0%)		1/50 (2%)		1/50 (2%)
Hypokalemia	1/48 (2.1%)		1/50 (2%)		0/50 (0%)
Musculoskeletal and connective tissue disorders
Muscle weakness lower limb	0/48 (0%)		1/50 (2%)		0/50 (0%)
Nervous system disorders
Nervous system disorders - Other	0/48 (0%)		1/50 (2%)		0/50 (0%)
Psychiatric disorders
Anxiety	0/48 (0%)		1/50 (2%)		0/50 (0%)
Renal and urinary disorders
Acute kidney injury	1/48 (2.1%)		0/50 (0%)		1/50 (2%)
Respiratory, thoracic and mediastinal disorders
Atelectasis	0/48 (0%)		1/50 (2%)		0/50 (0%)
Cough	1/48 (2.1%)		0/50 (0%)		0/50 (0%)
Dyspnea	1/48 (2.1%)		1/50 (2%)		3/50 (6%)
Laryngeal stenosis	0/48 (0%)		1/50 (2%)		0/50 (0%)
Vascular disorders
Hypotension	1/48 (2.1%)		1/50 (2%)		0/50 (0%)
Thromboembolic event	2/48 (4.2%)		0/50 (0%)		0/50 (0%)
Other (Not Including Serious) Adverse Events
	Supportive Care		Liquid Manuka Honey		Lozenge Manuka Honey
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/48 (77.1%)		46/50 (92%)		38/50 (76%)
Blood and lymphatic system disorders
Anemia	15/48 (31.3%)		20/50 (40%)		13/50 (26%)
Gastrointestinal disorders
Constipation	13/48 (27.1%)		15/50 (30%)		10/50 (20%)
Diarrhea	9/48 (18.8%)		11/50 (22%)		3/50 (6%)
Dry mouth	3/48 (6.3%)		5/50 (10%)		2/50 (4%)
Dyspepsia	10/48 (20.8%)		6/50 (12%)		2/50 (4%)
Dysphagia	17/48 (35.4%)		20/50 (40%)		17/50 (34%)
Esophageal pain	2/48 (4.2%)		8/50 (16%)		3/50 (6%)
Esophagitis	19/48 (39.6%)		18/50 (36%)		13/50 (26%)
Gastroesophageal reflux disease	0/48 (0%)		5/50 (10%)		3/50 (6%)
Gastrointestinal disorders - Other	0/48 (0%)		3/50 (6%)		1/50 (2%)
Mucositis oral	2/48 (4.2%)		2/50 (4%)		5/50 (10%)
Nausea	16/48 (33.3%)		23/50 (46%)		11/50 (22%)
Vomiting	7/48 (14.6%)		6/50 (12%)		4/50 (8%)
General disorders
Fatigue	28/48 (58.3%)		28/50 (56%)		22/50 (44%)
Non-cardiac chest pain	1/48 (2.1%)		3/50 (6%)		0/50 (0%)
Pain	3/48 (6.3%)		6/50 (12%)		4/50 (8%)
Infections and infestations
Mucosal infection	0/48 (0%)		3/50 (6%)		2/50 (4%)
Injury, poisoning and procedural complications
Dermatitis radiation	12/48 (25%)		7/50 (14%)		11/50 (22%)
Radiation recall reaction (dermatologic)	0/48 (0%)		3/50 (6%)		0/50 (0%)
Investigations
Alanine aminotransferase increased	1/48 (2.1%)		1/50 (2%)		4/50 (8%)
Alkaline phosphatase increased	2/48 (4.2%)		3/50 (6%)		1/50 (2%)
Creatinine increased	2/48 (4.2%)		5/50 (10%)		3/50 (6%)
Lymphocyte count decreased	7/48 (14.6%)		5/50 (10%)		2/50 (4%)
Neutrophil count decreased	6/48 (12.5%)		7/50 (14%)		10/50 (20%)
Platelet count decreased	4/48 (8.3%)		9/50 (18%)		11/50 (22%)
Weight loss	4/48 (8.3%)		8/50 (16%)		3/50 (6%)
White blood cell decreased	8/48 (16.7%)		13/50 (26%)		8/50 (16%)
Metabolism and nutrition disorders
Anorexia	10/48 (20.8%)		17/50 (34%)		5/50 (10%)
Dehydration	6/48 (12.5%)		8/50 (16%)		5/50 (10%)
Hyperglycemia	2/48 (4.2%)		7/50 (14%)		1/50 (2%)
Hypoalbuminemia	5/48 (10.4%)		5/50 (10%)		5/50 (10%)
Hypocalcemia	2/48 (4.2%)		3/50 (6%)		1/50 (2%)
Hypokalemia	4/48 (8.3%)		5/50 (10%)		3/50 (6%)
Hypomagnesemia	2/48 (4.2%)		3/50 (6%)		3/50 (6%)
Hyponatremia	4/48 (8.3%)		6/50 (12%)		3/50 (6%)
Musculoskeletal and connective tissue disorders
Back pain	2/48 (4.2%)		4/50 (8%)		0/50 (0%)
Chest wall pain	2/48 (4.2%)		4/50 (8%)		1/50 (2%)
Nervous system disorders
Dizziness	3/48 (6.3%)		5/50 (10%)		2/50 (4%)
Dysgeusia	6/48 (12.5%)		8/50 (16%)		4/50 (8%)
Headache	5/48 (10.4%)		4/50 (8%)		3/50 (6%)
Peripheral sensory neuropathy	6/48 (12.5%)		3/50 (6%)		2/50 (4%)
Psychiatric disorders
Anxiety	4/48 (8.3%)		3/50 (6%)		2/50 (4%)
Depression	1/48 (2.1%)		4/50 (8%)		0/50 (0%)
Insomnia	6/48 (12.5%)		5/50 (10%)		2/50 (4%)
Respiratory, thoracic and mediastinal disorders
Cough	12/48 (25%)		22/50 (44%)		11/50 (22%)
Dyspnea	8/48 (16.7%)		17/50 (34%)		13/50 (26%)
Hiccups	1/48 (2.1%)		2/50 (4%)		3/50 (6%)
Hoarseness	3/48 (6.3%)		2/50 (4%)		1/50 (2%)
Voice alteration	0/48 (0%)		3/50 (6%)		3/50 (6%)
Wheezing	0/48 (0%)		3/50 (6%)		1/50 (2%)
Skin and subcutaneous tissue disorders
Alopecia	3/48 (6.3%)		1/50 (2%)		1/50 (2%)
Dry skin	5/48 (10.4%)		1/50 (2%)		1/50 (2%)
Pruritus	5/48 (10.4%)		2/50 (4%)		1/50 (2%)
Rash acneiform	1/48 (2.1%)		3/50 (6%)		0/50 (0%)
Rash maculo-papular	4/48 (8.3%)		3/50 (6%)		1/50 (2%)
Vascular disorders
Hypotension	1/48 (2.1%)		3/50 (6%)		1/50 (2%)

Limitations/Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.