Management of Mandibular ORN: PENTO as Medical Treatment

• Sponsor: Hospital Vall d'Hebron (Other)
• Overall Status: Completed
• CT.gov ID: NCT02368457
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arms: 2
• Duration (Months): 23
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

Mandibular osteoradionecrosis, despite its low incidence, remains being the most problematic and irreversible complication after head and neck radiotherapy with no medical treatment to limit or reduce symptoms.

Different clinical trials have shown a significant scientific evidence that the treatment with pentoxifylline + tocopherol achieves a certain effectiveness in the treatment of the tissue fibrosis. This study proposes to use this drugs to determine if there is healing of mandibular osteoradionecrosis and/or a symptomatic improvement as well.

Condition or Disease	Intervention/Treatment	Phase
Osteoradionecrosis	Drug: Pentoxifylline and Tocopherol	Phase 4

Detailed Description

Mandibular osteoradionecrosis which occurs after the use of radiation therapy for the treatment of head and neck cancer remains being the most problematic and irreversible complication despite its low incidence with no medical treatment to limit or reduce symptoms.

Clinical trials conducted to date have shown a significant scientific evidence that the treatment with pentoxifylline + tocopherol achieves a certain effectiveness in the treatment of the tissue fibrosis that have been irradiated based on the properties of this drugs in increased tissue oxygenation and their antioxidant effect.

The aim of this study is to determine if there is a clinical improvement of mandibular osteoradionecrosis using Pentoxifylline in combination with Tocopherol as treatment because, currently, there is no effective treatment to achieve bone healing and/or a symptomatic improvement.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Advances in the Management of Mandibular Osteoradionecrosis: Pentoxifylline and Tocopherol as Medical Treatment
• Study Start Date: Feb 1, 2016
• Actual Primary Completion Date: Feb 1, 2016
• Actual Study Completion Date: Jan 1, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Pentoxifylline and Tocopherol Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months.	Drug: Pentoxifylline and Tocopherol; pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).; Other Names: PENTO
No Intervention: CONTROL No drug treatment

Outcome Measures

Primary Outcome Measures

1. Bone and/or Tissue Healing as Measured With the Classification of ORN Stages, Area of Bone Exposed (mm2) and Radiological Findings (OPG). [From baseline to 1, 3, 6, and 9 months of starting treatment]

   Clinical healing assessment as measured with the classification of ORN stages, area of bone exposed (mm2) and radiological findings (OPG). Intraoral bone exposure is measured in mm2.

Secondary Outcome Measures

1. Clinical Symptoms Evaluation, Measured Using the LENT-SOMA Scale [From baseline to 1,3, 6, 9 months of starting treatment]

   Evaluation of symptoms improvement using the LENT-SOMA scale (Late Effect Normal Tissue Task Force / Subjective, Objective, Management, Analytic scale). To examine the LENT/SOMA scale prospectively using interviews and questionnaires Assessments were made from baseline to 1, 3, 6 and 9 months of starting treatments. The acceptability and feasibility of using the scales was examined using compliance in completion of the questionnaires. Maximum score: 36 Minimum score: 0 Questionnaires have been completed for 24 patients after treatment. Higher values represents worse outcome. Scale categories: Subjective: pain, nutritional problems, difficulty in mouth openning. Objective: bone exposure, trismus, Management: analgesic treatment, oral treatment, nutrition. Analytic: radiological findings.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Over 18 years and under 90 years old.

• Patients who have received radiotherapy after being diagnosed with head and neck cancer and currently are diagnosticated of mandibular osteoradionecrosis (any clinical stage)

• Follow-up for at least a year after the radiation treatment is completed.

• Absence of tumor at the time of recruitment.

• Patients with the capacity to give informed consent

Exclusion Criteria:

• Allergy or hypersensitivity to Pentoxifylline or others xanthines, or to Tocopherol (vitamin E).

• Patients taking oral anticoagulants (acenocoumarol, warfarin).

• Known hemorrhagic/coagulation disorder.

• Vitamin K deficiency due to any cause.

• Use of estrogens oral contraceptives.

• Serious bleeding or extensive retinal hemorrhage.

• Ischaemic heart diseases, including recent Myocardial Infarction.

• Serious cardiac arrhythmia.

• Severe LIVER DISEASE.

• Severe renal failure (creatinine clearance <30 mL/min).

• Hypotension.

• Female patients who are pregnant or lactating

• Any other situation or condition that, in the opinion of the INVESTIGATOR, may interfere with optimal PARTICIPATION in the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Vall d'Hebrón Hospital	Barcelona		Spain	08035

Sponsors and Collaborators

• Hospital Vall d'Hebron

Investigators

• Principal Investigator: Miriam Martos-Fernandez, MD, Oral and Maxillofacial Surgery (Vall d'Hebrón Hospital)

Study Documents (Full-Text)

None provided.

More Information

Publications

• Delanian S, Chatel C, Porcher R, Depondt J, Lefaix JL. Complete restoration of refractory mandibular osteoradionecrosis by prolonged treatment with a pentoxifylline-tocopherol-clodronate combination (PENTOCLO): a phase II trial. Int J Radiat Oncol Biol Phys. 2011 Jul 1;80(3):832-9. doi: 10.1016/j.ijrobp.2010.03.029. Epub 2010 Jul 16.
• Delanian S, Depondt J, Lefaix JL. Major healing of refractory mandible osteoradionecrosis after treatment combining pentoxifylline and tocopherol: a phase II trial. Head Neck. 2005 Feb;27(2):114-23.
• Robard L, Louis MY, Blanchard D, Babin E, Delanian S. Medical treatment of osteoradionecrosis of the mandible by PENTOCLO: preliminary results. Eur Ann Otorhinolaryngol Head Neck Dis. 2014 Dec;131(6):333-338. doi: 10.1016/j.anorl.2013.11.006. Epub 2014 Jun 30.

• Responsible Party: Miriam Martos-Fernandez, Oral and Maxillofacial Surgeon, Hospital Vall d'Hebron
• ClinicalTrials.gov Identifier: NCT02368457
• Other Study ID Numbers: ORN-2014-16
• First Posted: Feb 23, 2015
• Last Update Posted: Mar 22, 2018
• Last Verified: Feb 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Miriam Martos-Fernandez, Oral and Maxillofacial Surgeon, Hospital Vall d'Hebron: Mandibular osteoradionecrosis; Tocopherol; pentoxifylline; vitamine E; wounds and injuries; antioxidants; free radical scavengers; radiation-protective agents; vasodilatadors agents; osteonecrosis; mandible; extraoral fistula; exposed bone; necrotic bone; head and neck radiotherapy
• Additional relevant MeSH terms: Osteoradionecrosis; Tocopherols; Vitamin E; Tocotrienols; alpha-Tocopherol; Pentoxifylline

Study Results

Participant Flow

Arm/Group Title	Pentoxifylline and Tocopherol	Control Group
Arm/Group Description	Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months. Pentoxifylline and Tocopherol: pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).	No drug treatment
Period Title: Overall Study
STARTED	12	12
COMPLETED	12	12
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Pentoxifylline and Tocopherol	Control Group	Total
Arm/Group Description	Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months. Pentoxifylline and Tocopherol: pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).	No drug treatment	Total of all reporting groups
Overall Participants	12	12	24
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57 (10)	55 (10)	56 (10)
Sex: Female, Male (Count of Participants)
Female	2 16.7%	2 16.7%	4 16.7%
Male	10 83.3%	10 83.3%	20 83.3%
Exposed bone (mm^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mm^2]	10 (10)	15 (10)	12.5 (10)

Outcome Measures

1. Primary Outcome

Title	Bone and/or Tissue Healing as Measured With the Classification of ORN Stages, Area of Bone Exposed (mm2) and Radiological Findings (OPG).
Description	Clinical healing assessment as measured with the classification of ORN stages, area of bone exposed (mm2) and radiological findings (OPG). Intraoral bone exposure is measured in mm2.
Time Frame	From baseline to 1, 3, 6, and 9 months of starting treatment

Outcome Measure Data

Analysis Population Description

mean of intraoral bone exposure (measured in mm2) from baseline to 1, 3, 6, 9, 12 and 18 months of starting treatment

Arm/Group Title	Pentoxifylline and Tocopherol	Control Group
Arm/Group Description	Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months. Pentoxifylline and Tocopherol: pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).	Standard treatment
Measure Participants	12	12
1 month of starting treatment	14	15
3 month of starting treatment	13	15
6 month of starting treatment	11.5	15
9 month of starting treatment	10	15

2. Secondary Outcome

Title	Clinical Symptoms Evaluation, Measured Using the LENT-SOMA Scale
Description	Evaluation of symptoms improvement using the LENT-SOMA scale (Late Effect Normal Tissue Task Force / Subjective, Objective, Management, Analytic scale). To examine the LENT/SOMA scale prospectively using interviews and questionnaires Assessments were made from baseline to 1, 3, 6 and 9 months of starting treatments. The acceptability and feasibility of using the scales was examined using compliance in completion of the questionnaires. Maximum score: 36 Minimum score: 0 Questionnaires have been completed for 24 patients after treatment. Higher values represents worse outcome. Scale categories: Subjective: pain, nutritional problems, difficulty in mouth openning. Objective: bone exposure, trismus, Management: analgesic treatment, oral treatment, nutrition. Analytic: radiological findings.
Time Frame	From baseline to 1,3, 6, 9 months of starting treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Pentoxifylline and Tocopherol	CONTROL
Arm/Group Description	Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months. Pentoxifylline and Tocopherol: pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).	No drug treatment
Measure Participants	12	12
1 month of starting treatment	14.5	15.5
3 month of starting treatment	14	15.5
6 month of starting treatment	14	15.5
9 month of starting treatment	13.3	15.5

Adverse Events

Time Frame	18 months
Arm/Group Title	Pentoxifylline and Tocopherol		Control Group
Arm/Group Description	Drug: pentoxifylline with tocopherol Combination of pentoxifylline and tocopherol during a minimum of 6 months and a maximum of 24 months. Pentoxifylline and Tocopherol: pentoxifylline with tocopherol Pentoxifylline 800 mg/day, oral (1cp 400 mg twice a day) + Vitamin E (alfa-tocopherol) 1000 UI/day, oral (1cp 400UI twice a day + 1cp200UI once a day) during 24 months (maximum).		Standard treatment
All Cause Mortality
	Pentoxifylline and Tocopherol		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Pentoxifylline and Tocopherol		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)
Other (Not Including Serious) Adverse Events
	Pentoxifylline and Tocopherol		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)

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.