LLLTHSCT: Low-level Laser Therapy on Inflammatory Mediators During Chemotherapy-induced Oral Mucositis

• Sponsor: Universidade Federal de Goias (Other)
• Overall Status: Completed
• CT.gov ID: NCT02050373
• Collaborator: Federal University of Minas Gerais (Other), Araujo Jorge Hospital (Other)
• Enrollment: 51
• Arms: 2
• Duration (Months): 61

Study Details

Study Description

Brief Summary

The aim of the study is to evaluate the effect of low-level laser therapy (LLLT) on the severity of oral mucositis (OM) and inflammatory mediators (pro- and anti-inflammatory cytokines, metalloproteinases and growth factors) levels in saliva and blood; furthermore, analyze the effect of LLLT in product modulation of oxidative stress and cell damage from the oral mucosa transplant patients.

Condition or Disease	Intervention/Treatment	Phase
Oral Mucositis	Radiation: Low-Level laser	N/A

Detailed Description

This is a randomized clinical trial in which the proposed analysis will be performed from saliva samples of patients transplanted bone marrow, divided into two different groups (control and laser) and collected at different times during the hospitalization of the patient. the group laser receive prophylactic laser therapy, in order to evaluate the effects of LLLT in inflammatory mediators (cytokines pro- and anti-inflammatory) as well as their effect on modulation of oxidative stress products and cell damage (nitric oxide, myeloperoxidase, interleukin-8).

Study Design

• Study Type: Interventional
• Actual Enrollment: 51 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Effect of Low-level Laser Therapy on Inflammatory Mediators Release During Chemotherapy-induced Oral Mucositis: a Randomized Study
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Feb 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Low-Level laser In the laser group, an indium phosphide, galium and aluminum (InGaAIP) diode laser (660nm, 40mW, 0.16 J, 4 J/cm2) was used to irradiate oral mucosa. Subjects received the LLLT from the first day of the conditioning regimen and continued until D+7. Laser therapy was applied by a single dentist expertise in laser irradiation. The tip touched the mucosa of the lips, right and left buccal mucosa, right and left lateral tongue, ventral tongue and buccal floor, giving a total of 10 points per region.	Radiation: Low-Level laser; Application of laser therapy in low power mucosa jugal right and left upper and lower labial mucosa, floor of the mouth, tongue side of the right and left and belly of the tongue.
No Intervention: Control In the control group, patients receive only the preventive protocol bone marrow transplant industry, consisting of mouthwashes and sodium fluoride. For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.

Outcome Measures

Primary Outcome Measures

1. Severity of Oral Mucositis [On day of the transplant (D0), on seventh day after the transplant (D7) and discharge of the patient (HD) or until day 20 (D+20).]

   A trained clinical member of the team who was blind to the randomization allocation scores the degree of OM, during the hospitalization, in accordance to the World Health Organization (WHO) mucositis scale as follow: grade 0, no signs or symptoms; grade 1, painless ulcers, erythema, or mild soreness; grade 2, painful erythema, edema, or ulceration but the patient is able to eat; grade 3, mucosal damage and the patient is able to ingest only liquids; and grade 4, severe mucosa damage and the patient requires parenteral or enteral support.

Secondary Outcome Measures

1. Level of Inflammatory Mediators [The samples were collected at three different moments of treatment: at the time of admission (AD), on the seventh day after transplantation (D+7), and on the day of discharge (with neutrophil >0.5 × 109/l for two consecutive days) (HD).]

   Saliva was collected in the morning, and patients were instructed to gargle with filtered water prior to collection. All the saliva produced in a 5-min interval was collected in a sterile tube. The saliva samples were then centrifuged at 1500 rpm for 10 min, and the total volumes measured with a micropipette. The supernatant was transferred to two other sterile tubes and a phosphate-buffered saline (PBS) solution (1: 1), containing protease inhibitors (0.1 mmol/1 EDTA, 0.001 mg/ml aprotinin A, and 0.05% Tween 20) which was added to one while the other maintained its pure saliva. All aliquots were frozen at -80°C to await analysis.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 14 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Schedule to receive myeloablative conditioning regimens using chemotherapy; oral mucosa lining intact on the first day of the conditioning regimen;

Exclusion Criteria:

• Patients who presented with oral oral ulceration or erosion, active oral, viral, bacterial, or fungal infections on admission, or active oral bleeding which was uncontrollable during laser therapy or had required oral tracheal intubation during hospitalization in the HSCT Unit.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Universidade Federal de Goias
• Federal University of Minas Gerais
• Araujo Jorge Hospital

Investigators

• Principal Investigator: Geisa BL Silva, Master, Universidade Federal de Goias
• Study Director: Aline C Batista, Doctor, Universidade Federal de Goias
• Principal Investigator: Daniella RN Salvador, Universidade Federal de Goias

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Geisa Badauy Lauria Silva, Principal investigator, Universidade Federal de Goias
• ClinicalTrials.gov Identifier: NCT02050373
• Other Study ID Numbers: 382/2011
• First Posted: Jan 30, 2014
• Last Update Posted: Jan 22, 2021
• Last Verified: Jan 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Keywords provided by Geisa Badauy Lauria Silva, Principal investigator, Universidade Federal de Goias: Mucositis; inflammation; Chemotherapy; Hematopoietic stem cell transplant; Low level laser therapy; oxidative stress
• Additional relevant MeSH terms: Mucositis; Stomatitis

Study Results

Participant Flow

Recruitment Details	This study enrolled patients admitted to the Bone Marrow Transplant Unit at Hospital Araújo Jorge/Goiás Combat Cancer Association (TMO/HAJ/ACCG), between February 2012 and July 2016.
Pre-assignment Detail	The patients recruited underwent block randomization and were allocated to two groups: one which would receive the low level laser therapy protocol (LLLT group) and one which would not, only the oral hygiene guidelines described above (control group).

Arm/Group Title	Low-Level Laser	Controll
Arm/Group Description	In the laser group, an indium phosphide, galium and aluminum (InGaAIP) diode laser (660nm, 40mW, 0.16 J, 4 J/cm2) was used to irradiate oral mucosa. Subjects received the LLLT from the first day of the conditioning regimen and continued until D+7. Laser therapy was applied by a single dentist expertise in laser irradiation. The tip touched the mucosa of the lips, right and left buccal mucosa, right and left lateral tongue, ventral tongue and buccal floor, giving a total of 10 points per region. Low-Level laser: Application of laser therapy in low power mucosa jugal right and left upper and lower labial mucosa, floor of the mouth, tongue side of the right and left and belly of the tongue.	In the control group, patients receive only the preventive protocol bone marrow transplant industry, consisting of mouthwashes and sodium fluoride. For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.
Period Title: Overall Study
STARTED	34	34
COMPLETED	27	24
NOT COMPLETED	7	10

Baseline Characteristics

Arm/Group Title	Low-Level Laser	Control	Total
Arm/Group Description	In the laser group, an indium phosphide, galium and aluminum (InGaAIP) diode laser (660nm, 40mW, 0.16 J, 4 J/cm2) was used to irradiate oral mucosa. 27 Subjects received the LLLT from the first day of the conditioning regimen and continued until D+7. Laser therapy was applied by a single dentist expertise in laser irradiation. The tip touched the mucosa of the lips, right and left buccal mucosa, right and left lateral tongue, ventral tongue and buccal floor, giving a total of 10 points per region. Low-Level laser: Application of laser therapy in low power mucosa jugal right and left upper and lower labial mucosa, floor of the mouth, tongue side of the right and left and belly of the tongue.	In the control group, 24 patients receive only the preventive protocol bone marrow transplant industry, consisting of mouthwashes and sodium fluoride. For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.	Total of all reporting groups
Overall Participants	27	24	51
Age (Count of Participants)
<=18 years	2 7.4%	0 0%	2 3.9%
Between 18 and 65 years	24 88.9%	24 100%	48 94.1%
>=65 years	1 3.7%	0 0%	1 2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41 (14.9)	42 (17.8)	41 (15.34)
Sex: Female, Male (Count of Participants)
Female	12 44.4%	13 54.2%	25 49%
Male	15 55.6%	11 45.8%	26 51%
Race and Ethnicity Not Collected (Count of Participants)
Count of Participants [Participants]	0 0%
Region of Enrollment (participants) [Number]
Brazil	27 100%	24 100%	51 100%

Outcome Measures

1. Primary Outcome

Title	Severity of Oral Mucositis
Description	A trained clinical member of the team who was blind to the randomization allocation scores the degree of OM, during the hospitalization, in accordance to the World Health Organization (WHO) mucositis scale as follow: grade 0, no signs or symptoms; grade 1, painless ulcers, erythema, or mild soreness; grade 2, painful erythema, edema, or ulceration but the patient is able to eat; grade 3, mucosal damage and the patient is able to ingest only liquids; and grade 4, severe mucosa damage and the patient requires parenteral or enteral support.
Time Frame	On day of the transplant (D0), on seventh day after the transplant (D7) and discharge of the patient (HD) or until day 20 (D+20).

Outcome Measure Data

Analysis Population Description

Oral Mucositis (OM) was evaluated on admission (AD), day 7 (D+7) and hospital discharge (HD) of the all patients. The severity of OM was scored in accordance with the World Health Organization (WHO), being represented by ordinal qualitative data.

Arm/Group Title	Low-Level Laser	Control
Arm/Group Description	In the laser group, an indium phosphide, galium and aluminum (InGaAIP) diode laser (660nm, 40mW, 0.16 J, 4 J/cm2) was used to irradiate oral mucosa. Subjects received the LLLT from the first day of the conditioning regimen and continued until D+7. Laser therapy was applied by a single dentist expertise in laser irradiation. The tip touched the mucosa of the lips, right and left buccal mucosa, right and left lateral tongue, ventral tongue and buccal floor, giving a total of 10 points per region. Application of laser therapy in low power mucosa jugal right and left upper and lower labial mucosa, floor of the mouth, tongue side of the right and left and belly of the tongue.	In the control group, patients receive instructions on the oral hygiene protocol (dental brushing after meals, dental flossing once a day and an alcohol-free 0.12% mouthwash twice a day). For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.
Measure Participants	27	24
Grade 0	27 100%	24 100%
Grade 1	0 0%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%
Grade 0	22 81.5%	0 0%
Grade 1	0 0%	10 41.7%
Grade 2	5 18.5%	10 41.7%
Grade 3	0 0%	4 16.7%
Grade 4	0 0%	0 0%
Grade 0	27 100%	24 100%
Grade 1	0 0%	0 0%
Grade 2	0 0%	0 0%
Grade 3	0 0%	0 0%
Grade 4	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-Level Laser, Control
	Comments	The Pearson chi-square (χ2) or Fisher's Exact tests were used, at three different times (AD, D7, HD), to analyze the oral mucositis severity in the comparison between the LLLT and control groups. Statistical analysis was not performed for each grade of oral mucositis separately.
	Type of Statistical Test	Other
	Comments	For the comparison between the LLLT and control groups the Pearson chi-square (χ2) or Fisher's Exact tests were used.
Statistical Test of Hypothesis	p-Value	<0.05
	Comments
	Method	Fisher Exact
	Comments

2. Secondary Outcome

Title	Level of Inflammatory Mediators
Description	Saliva was collected in the morning, and patients were instructed to gargle with filtered water prior to collection. All the saliva produced in a 5-min interval was collected in a sterile tube. The saliva samples were then centrifuged at 1500 rpm for 10 min, and the total volumes measured with a micropipette. The supernatant was transferred to two other sterile tubes and a phosphate-buffered saline (PBS) solution (1: 1), containing protease inhibitors (0.1 mmol/1 EDTA, 0.001 mg/ml aprotinin A, and 0.05% Tween 20) which was added to one while the other maintained its pure saliva. All aliquots were frozen at -80°C to await analysis.
Time Frame	The samples were collected at three different moments of treatment: at the time of admission (AD), on the seventh day after transplantation (D+7), and on the day of discharge (with neutrophil >0.5 × 109/l for two consecutive days) (HD).

Outcome Measure Data

Analysis Population Description

Were admitted patients had to be at least 14 years of age, scheduled for autologous or allogeneic HSCT and planned treatment consisting of a myeloablative conditioning regimen with high-dose chemotherapy (HDC), without radiotherapy. Their oral mucosal lining had to be intact, and they had to have no infectious or other associated pathologies.

Arm/Group Title	LLLT	Control
Arm/Group Description	Patients in the LLLT group received applications from the first day of the conditioning regimen and continued every day until the seventh post-transplant day (D+7), at approximately the same time each day. Applications were made by the same professional expert laser therapy and in compliance with all necessary biosafety protocols.	In the control group, patients receive instructions on the oral hygiene protocol (dental brushing after meals, dental flossing once a day and an alcohol-free 0.12% mouthwash twice a day). For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.
Measure Participants	27	24
CXCL-8 AD	1733	185
CXCL-8 D7	730	201
CXCL-8 HD	1264	195
NO AD	127	54
NO D7	68	68
NO HD	80	53
MPO AD	62	60
MPO D7	7	4
MPO HD	61	24

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Low-Level Laser, Control
	Comments
	Type of Statistical Test	Other
	Comments	Student's t test was used to numerical variables with normal distribution. The Mann-Whitney test was used to compare the cytokine values of the two groups (control and laser). The Friedman test was used to indicate differences by comparing cytokine levels at different times of assessment within each group. The Friedman and Wilcoxon tests were used for paired analyzes of the saliva collection times in the groups. All tests were used to compare the groups at the three different times (AD, D7, HD).
Statistical Test of Hypothesis	p-Value	<0.05
	Comments	p<0,05
	Method	Wilcoxon (Mann-Whitney)
	Comments

Adverse Events

Time Frame	The patients was evaluated daily from the day of transplantation or infusion of bone marrow (D0) until day 20 (D+20) or discharge of the patient.
Arm/Group Title	Low-Level Laser		Control
Arm/Group Description	In the laser group, an indium phosphide, galium and aluminum (InGaAIP) diode laser (660nm, 40mW, 0.16 J, 4 J/cm2) was used to irradiate oral mucosa. Subjects received the LLLT from the first day of the conditioning regimen and continued until D+7. Laser therapy was applied by a single dentist expertise in laser irradiation. The tip touched the mucosa of the lips, right and left buccal mucosa, right and left lateral tongue, ventral tongue and buccal floor, giving a total of 10 points per region. Application of laser therapy in low power mucosa jugal right and left upper and lower labial mucosa, floor of the mouth, tongue side of the right and left and belly of the tongue.		In the control group, patients receive instructions on the oral hygiene protocol (dental brushing after meals, dental flossing once a day and an alcohol-free 0.12% mouthwash twice a day). For ethical reasons, individuals who present oral mucositis grade 2 (WHO) will receive LLLT.
All Cause Mortality
	Low-Level Laser		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/34 (8.8%)		3/34 (8.8%)
Serious Adverse Events
	Low-Level Laser		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/34 (11.8%)		7/34 (20.6%)
General disorders
Need for oral tracheal intubation during hospitalization	3/34 (8.8%)		7/34 (20.6%)
Nervous system disorders
Mental confusion	1/34 (2.9%)		0/34 (0%)
Other (Not Including Serious) Adverse Events
	Low-Level Laser		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/34 (0%)		0/34 (0%)

Limitations/Caveats

The clinical trials with cancer patients submitted to HSCT include difficulty in homogenizing the underlying disease and treatment protocols and the influence of the underlying disease on the blood or salivary levels of chemical mediators.

More Information

Certain Agreements

Principal Investigators are NOT 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.