Evaluation of Efficacy and Mechanisms of an Antiinflammatory Intervention for Chemotherapy Related Mucosal Injury

• Sponsor: National Institute of Nursing Research (NINR) (NIH)
• Overall Status: Terminated
• CT.gov ID: NCT00031551
• Collaborator: (none)
• Enrollment: 27
• Locations: 2
• Arms: 3
• Duration (Months): 101
• Patients Per Site: 13.5
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study consisted of two parts: the pilot study and the main study. The purpose of the pilot study is to demonstrate the effectiveness of planned laboratory techniques to assess for TNF-alpha gene expression from unstimulated saliva, plasma, and mucosal epithelial cells in patients who have chemotherapy-related stomatitis.

Main Study Description: Stomatitis is defined as inflammation of the mucous membranes of the oral cavity and oropharynx characterized by tissue erythema, edema, and atrophy, often progressing to ulceration. Stomatitis is a biologically complex, multifactorial, cancer treatment-related oral condition experienced by many oncology patients, which often leads to a cascade of negative sequelae including oropharyngeal pain, critical treatment alterations or cessation, and decreased quality of life. The optimal treatment strategies for stomatitis have not been established. There is a critical need to examine the pathogenesis of and to evaluate interventions for stomatitis and related acute oropharyngeal pain in the randomized controlled clinical trial setting using valid and reliable stomatitis assessment tools to both advance the science of cancer treatment-related oral toxicities and improve patient care. Therefore, the purpose of this randomized controlled clinical trial is to elucidate the role of inflammation in stomatitis by testing the effects of a novel tumor necrosis factor (TNF) fusion protein etanercept, (Enbrel, Immunex Corporation, Seattle, WA) on the incidence and severity of stomatitis. The actions of this fusion protein, which binds specifically to TNF preventing its interaction with cellular receptors and altering the inflammatory cascade, may provide insight into the role of inflammation in stomatitis. An etanercept effect is defined as a prevention or amelioration of stomatitis and acute oropharyngeal pain and/or changes in levels of tissue mediators. If stomatitis is primarily a consequence of a mucosal inflammatory response, then we hypothesize that this oral condition will be responsive to binding of TNF(alpha). Elaboration of the role of inflammatory cell signaling associated with stomatitis and the effect of TNF(alpha) may elucidate the mechanisms related to the pathogenesis of stomatitis and to other mucosal conditions.

Patients who are scheduled to receive autologous or allogenic peripheral blood stem cell or bone marrow transplant will be invited to participate in this study during a regularly scheduled pre-treatment visit. Written informed consent will be obtained from all participants. Patients will be randomized to receive either etanercept mouthwash or placebo, which will both be administered by protocol schedule. Stomatitis and oropharyngeal pain will be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course. TNF(alpha) levels in buccal mucosa, analyzed by reverse transcriptase polymerase chain reaction techniques, and blood levels of pro-inflammatory cytokines, growth factors, and inflammatory mediators will also be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course.

Condition or Disease	Intervention/Treatment	Phase
Stomatitis	Drug: Etanercept; Drug: Placebo	Phase 2

Detailed Description

This study consisted of two parts: the pilot study and the main study. The purpose of the pilot study is to demonstrate the effectiveness of planned laboratory techniques to assess for TNF-alpha gene expression from unstimulated saliva, plasma, and mucosal epithelial cells in patients who have chemotherapy-related stomatitis.

Main Study Description: Stomatitis is defined as inflammation of the mucous membranes of the oral cavity and oropharynx characterized by tissue erythema, edema, and atrophy, often progressing to ulceration. Stomatitis is a biologically complex, multifactorial, cancer treatment-related oral condition experienced by many oncology patients, which often leads to a cascade of negative sequelae including oropharyngeal pain, critical treatment alterations or cessation, and decreased quality of life. The optimal treatment strategies for stomatitis have not been established. There is a critical need to examine the pathogenesis of and to evaluate interventions for stomatitis and related acute oropharyngeal pain in the randomized controlled clinical trial setting using valid and reliable stomatitis assessment tools to both advance the science of cancer treatment-related oral toxicities and improve patient care. Therefore, the purpose of this randomized controlled clinical trial is to elucidate the role of inflammation in stomatitis by testing the effects of a novel tumor necrosis factor (TNF) fusion protein etanercept, (Enbrel) (Registered Trademark), Immunex Corporation, Seattle, WA) on the incidence and severity of stomatitis. The actions of this fusion protein, which binds specifically to TNF preventing its interaction with cellular receptors and altering the inflammatory cascade, may provide insight into the role of inflammation in stomatitis. An etanercept effect is defined as a prevention or amelioration of stomatitis and acute oropharyngeal pain and/or changes in levels of tissue mediators. If stomatitis is primarily a consequence of a mucosal inflammatory response, then we hypothesize that this oral condition will be responsive to binding of TNFa. Elaboration of the role of inflammatory cell signaling associated with stomatitis and the effect of TNFa may elucidate the mechanisms related to the pathogenesis of stomatitis and to other mucosal conditions.

Patients who are scheduled to receive autologous or allogeneic peripheral blood stem cell or bone marrow transplant will be invited to participate in this study during a regularly scheduled pre-treatment visit. Written informed consent will be obtained from all participants. Patients will be randomized to receive either etanercept 2.5mg in 20cc mouthwash or placebo 20cc mouthwash, which will both be administered by protocol schedule. Stomatitis and oropharyngeal pain will be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course. TNFa levels in buccal mucosa, analyzed by real time polymerase chain reaction techniques, and blood levels of pro-inflammatory cytokines, growth factors, and inflammatory mediators will also be measured at baseline and at specified post-chemotherapy time points corresponding with the predicted stomatitis onset, peak, and healing time course.

Study Design

• Study Type: Interventional
• Actual Enrollment: 27 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: Evaluation of Efficacy and Mechanisms of an Anti-Inflammatory Intervention for Chemotherapy Related Mucosal Injury
• Study Start Date: Mar 1, 2002
• Actual Primary Completion Date: Aug 1, 2010
• Actual Study Completion Date: Aug 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Main Study: Etanercept Mouthwash Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first.	Drug: Etanercept; Other Names: Enbrel
Placebo Comparator: Main Study: Placebo Mouthwash Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first.	Drug: Placebo
No Intervention: Pilot Study Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.

Outcome Measures

Primary Outcome Measures

1. What is the Clinical Efficacy of an Etanercept Mouthwash Used for the Treatment of Autologous or Allogeneic Peripheral Blood Stem Cell Transplant or Bone Marrow Transplant Treatment-related Stomatitis? [2 years]

   Clinical efficacy will be determined by measurement of stomatitis grade and oropharyngeal pain.

Secondary Outcome Measures

1. What is the Toxicity of an Etanercept Mouthwash Used for the Treatment of Autologous or Allogeneic Peripheral Blood Stem Cell Transplant or Bone Marrow Transplant Treatment -Related Stomatitis? [2 years]

   Toxicity will be measured by the incidence of adverse events.

Other Outcome Measures

1. Pilot Study: Mean Ratings of Oral Mucositis-related Oropharyngeal Pain Intensity on Day 9 (+/- 24 Hours) After Conditioning Chemotherapy (CT) [Day 9 (+/- 24 hours) after conditioning chemotherapy]

   Subjects rated pain using the Painometer, a hand-held tool with a visual analogue scale to rate overall pain intensity and a list of 14 sensory and 11 affective pain descriptors ranked by intensity values from 1 - 5. Subjects look at the list of sensory and affective words and select words that describe their pain, including Oral Pain and Oral Pain with Swallowing. . The weighted scores assigned to the words are added to obtain a pain intensity score for the sensory and the affective components. The overall pain intensity is measured on a visual analogue scale which has a range of 1 - 10 with high scores indicating higher pain intensity. The sensory and affective pain scores are otained by adding all of the respective intensity values. The range of possible sensory scores is from 0 - 48 and the range of possible affective scores is from 0 - 37. The sensory and affective scores may be added together to obtain the total pain intensity score, which may range from 0 - 85.

2. Pilot Study: Percentage of Participants Using Word Descriptors of Sensory and Affective Pain Selected by Subjects on Day 9 (+/- 24 Hours) After Conditioning Chemotherapy [day 9 (+/- 24 hours) after conditioning chemotherapy]

   Participants selected from 14 word descriptors of sensory (S) pain and 11 word descriptors of affective (A) pain.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 16 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

• INCLUSION CRITERIA:

1. Male or female oncology patients who are enrolled in participating stomatogenic autologous or allogeneic PBSCT/BMT protocols, and are willing to participate in this study concurrently

2. Able to understand and sign protocol consent or assent

3. Age 16 years or older

EXCLUSION CRITERIA:

1. Pregnant or lactating females

2. Unable to follow oral rinsing directions

3. Intubation

4. Chronic use of medications confounding assessment of the inflammatory response (non-steroidal antiinflammatory drugs, antihistamines, and steroids- with the exception of decadron that is commonly used as an antiemetic in the PBSCT/BMT setting)

5. Pre-existing oral infection or upper respiratory infection that might maximize the possibility of an infection or sepsis contributing to a drug-related adverse event

6. Known hypersensitivity or allergic reaction to etanercept

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	National Institutes of Health Clinical Center, 9000 Rockville Pike	Bethesda	Maryland	United States	20892
2	Greenville Cancer Centers of the Carolinas	Greenville	South Carolina	United States	29615

Sponsors and Collaborators

• National Institute of Nursing Research (NINR)

Investigators

• Principal Investigator: Jane M Fall-Dickson, PhD, National Institute of Nursing Research, National Institutes of Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• NIH Clinical Center Detailed Web Page

Publications

• Dose AM. The symptom experience of mucositis, stomatitis, and xerostomia. Semin Oncol Nurs. 1995 Nov;11(4):248-55. Review.
• Seto BG, Kim M, Wolinsky L, Mito RS, Champlin R. Oral mucositis in patients undergoing bone marrow transplantation. Oral Surg Oral Med Oral Pathol. 1985 Nov;60(5):493-7.
• Woo SB, Sonis ST, Monopoli MM, Sonis AL. A longitudinal study of oral ulcerative mucositis in bone marrow transplant recipients. Cancer. 1993 Sep 1;72(5):1612-7.

• Responsible Party: National Institute of Nursing Research (NINR)
• ClinicalTrials.gov Identifier: NCT00031551
• Other Study ID Numbers: 020133; 02-NR-0133
• First Posted: Mar 8, 2002
• Last Update Posted: Dec 6, 2017
• Last Verified: Nov 1, 2017

• Keywords provided by National Institute of Nursing Research (NINR): Stomatitis; Oropharyngeal pain; TNF; Etanercept; Bone marrow transplantation; Chemotherapy; Cancer; Oral cavity; Oral mucous membranes; Randomized controlled clinical trial; Inflammation
• Additional relevant MeSH terms: Stomatitis; Etanercept

Study Results

Participant Flow

Arm/Group Title	Main Study Participants	Pilot Study
Arm/Group Description	Participants were randomized to one of the following two interventions but the study was not unblinded. Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first. Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first.	Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.
Period Title: Overall Study
STARTED	2	25
COMPLETED	0	25
NOT COMPLETED	2	0

Baseline Characteristics

Arm/Group Title	Main Study Participants	Pilot Study	Total
Arm/Group Description	Participants were randomized to one of the following two interventions but the study was not unblinded. Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first. Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first.	Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.	Total of all reporting groups
Overall Participants	2	25	27
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	59	46	NA
Sex: Female, Male (Count of Participants)
Female	0 0%	13 52%	13 48.1%
Male	2 100%	12 48%	14 51.9%
Race/Ethnicity, Customized (participants) [Number]
White	2 100%	16 64%	18 66.7%
Hispanic	0 0%	6 24%	6 22.2%
Black	0 0%	2 8%	2 7.4%
Asian/Pacific Islander	0 0%	1 4%	1 3.7%
Region of Enrollment (participants) [Number]
United States	2 100%	25 100%	27 100%
Education (participants) [Number]
Grade School	0 0%	2 8%	2 7.4%
High School	0 0%	5 20%	5 18.5%
Some College	0 0%	7 28%	7 25.9%
College Graduate	1 50%	7 28%	8 29.6%
Graduate School	1 50%	4 16%	5 18.5%
Cancer Diagnosis (participants) [Number]
Breast Cancer	0 0%	7 28%	7 25.9%
Non-Hodgkin's Lymphoma	1 50%	8 32%	9 33.3%
Hodgkin's Lymphoma	0 0%	4 16%	4 14.8%
Multiple Myeloma	1 50%	2 8%	3 11.1%
Leukemia	0 0%	4 16%	4 14.8%
Cancer stage (participants) [Number]
Stage II	0 0%	1 4%	1 3.7%
Stage III	1 50%	13 52%	14 51.9%
Stage IV	0 0%	5 20%	5 18.5%
Unstaged	0 0%	1 4%	1 3.7%
First Remission	0 0%	1 4%	1 3.7%
Second Remission	0 0%	1 4%	1 3.7%
Accelerated Phase	0 0%	1 4%	1 3.7%
Unknown	1 50%	2 8%	3 11.1%

Outcome Measures

1. Primary Outcome

Title	What is the Clinical Efficacy of an Etanercept Mouthwash Used for the Treatment of Autologous or Allogeneic Peripheral Blood Stem Cell Transplant or Bone Marrow Transplant Treatment-related Stomatitis?
Description	Clinical efficacy will be determined by measurement of stomatitis grade and oropharyngeal pain.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Participants withdrew and analyses were terminated before any data collected.

Arm/Group Title	Main Study: Etanercept Mouthwash	Main Study: Placebo Mouthwash
Arm/Group Description	Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first. Etanercept	Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first. Placebo
Measure Participants	0	0

2. Secondary Outcome

Title	What is the Toxicity of an Etanercept Mouthwash Used for the Treatment of Autologous or Allogeneic Peripheral Blood Stem Cell Transplant or Bone Marrow Transplant Treatment -Related Stomatitis?
Description	Toxicity will be measured by the incidence of adverse events.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Main Study Participants
Arm/Group Description	Participants were randomized to one of the following two interventions but the study was not unblinded. Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first. Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first.
Measure Participants	2
Number [event]	5

3. Other Pre-specified Outcome

Title	Pilot Study: Mean Ratings of Oral Mucositis-related Oropharyngeal Pain Intensity on Day 9 (+/- 24 Hours) After Conditioning Chemotherapy (CT)
Description	Subjects rated pain using the Painometer, a hand-held tool with a visual analogue scale to rate overall pain intensity and a list of 14 sensory and 11 affective pain descriptors ranked by intensity values from 1 - 5. Subjects look at the list of sensory and affective words and select words that describe their pain, including Oral Pain and Oral Pain with Swallowing. . The weighted scores assigned to the words are added to obtain a pain intensity score for the sensory and the affective components. The overall pain intensity is measured on a visual analogue scale which has a range of 1 - 10 with high scores indicating higher pain intensity. The sensory and affective pain scores are otained by adding all of the respective intensity values. The range of possible sensory scores is from 0 - 48 and the range of possible affective scores is from 0 - 37. The sensory and affective scores may be added together to obtain the total pain intensity score, which may range from 0 - 85.
Time Frame	Day 9 (+/- 24 hours) after conditioning chemotherapy

Outcome Measure Data

Analysis Population Description

One subject was in critical condition at day 9 after CT, preventing data collection at this time

Arm/Group Title	Pilot Study: Baseline Scores	Pilot Study: Day 9 After CT Scores
Arm/Group Description	Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.
Measure Participants	24	24
Oral Pain: Overall pain intensity	0.03 (0.16)	1.38 (2.36)
Oral Pain: Pain, Sensory Dimension	0.12 (0.60)	4.75 (11.58)
Oral Pain: Pain, affective Dimension	0.04 (0.20)	3.33 (9.35)
Oral Pain: Pain, Sensory and affective Dimensions	0.16 (0.80)	8.13 (19.79)
Pain with Swallowing: Overall pain intensity	0.03 (0.16)	2.28 (3.38)
Pain with Swallowing: Pain, Sensory Dimension	0.08 (0.40)	5.48 (11.69)
Pain with Swallowing: Pain, Affective Dimension	0 (0)	4.09 (10.25)
Pain with Swallowing:Sensory & Affective Dimension	0.08 (0.40)	9.61 (21.71)

4. Other Pre-specified Outcome

Title	Pilot Study: Percentage of Participants Using Word Descriptors of Sensory and Affective Pain Selected by Subjects on Day 9 (+/- 24 Hours) After Conditioning Chemotherapy
Description	Participants selected from 14 word descriptors of sensory (S) pain and 11 word descriptors of affective (A) pain.
Time Frame	day 9 (+/- 24 hours) after conditioning chemotherapy

Outcome Measure Data

Analysis Population Description

One subject was in critical condition at day 9 after CT, preventing data collection at this time

Arm/Group Title	Pilot Study
Arm/Group Description	Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.
Measure Participants	24
Sensory words: Cramping, radiation, sharp	4.2 210%
Sensory: Splitting, shooting, stabbing, tearing	8.3 415%
Sensory words: Dull, burning, crushing, pressing	12.5 625%
Sensory words: Aching	16.7 835%
Sensory words: Hurting	20.8 1040%
Sensory words: Sore	29.2 1460%
Sensory words: torturing, splitting, crushing	4.2 210%
S:Cramping, shooting, radiating, stabbing, tearing	8.3 415%
Sensory words: Dull, aching, pressing	12.5 625%
Sensory words: Hurting Group 2	16.7 835%
Sensory words: Burning, sharp	20.8 1040%
Sensory words: Sore Group 2	29.2 1460%
Affective words: Terrifying, torturing	4.2 210%
Affective: Killing, tiring, unbearable, sickening	8.3 415%
A: Nagging, agonizing, troublesome, miserable	12.5 625%
Affective words: Annoying	25.0 1250%
Affective words: Torturing	4.2 210%
Affective words: Killing, unbearable, terrifying	8.3 415%
A: Agonizing, troublesome, tiring, sickening	12.5 625%
Affective words: Miserable, nagging	16.7 835%
Affective words: Annoying Group 2	20.8 1040%

Adverse Events

Adverse Event Reporting Description	Adverse events were not assessed for the pilot study.
Arm/Group Title	Main Study Participants		Pilot Study
Arm/Group Description	Participants were randomized to one of the following two interventions but the study was not unblinded. Etanercept 2.5 mg in 20cc mouthwash is swished and spit by the participant every 6 hours. The experimental mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant (BMT) Day +14, whichever occurs first. Placebo 20cc mouthwash is swished and spit by the participant every 6 hours. The placebo mouthwash starts one day before conditioning chemotherapy is administered to the participant and continues until oral pain intensity and stomatitis severity scores are both 0, or by bone marrow transplant day (BMT) Day +14, whichever occurs first.		Participants were enrolled in the pilot study to collect descriptive data about pain perception and laboratory techniques.
All Cause Mortality
	Main Study Participants		Pilot Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Main Study Participants		Pilot Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/2 (0%)		0/0 (NaN)
Other (Not Including Serious) Adverse Events
	Main Study Participants		Pilot Study
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/2 (100%)		0/0 (NaN)
Gastrointestinal disorders
Nausea	2/2 (100%)		0/0 (NaN)
Diarrhea	2/2 (100%)		0/0 (NaN)
General disorders
Fatigue	1/2 (50%)		0/0 (NaN)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.