PentoxIfylline and Tocopherol for the Treatment of Post-radiotherapy Fibrosis in Head and Neck Cancer Patients

NCT03723291 | Completed Phase 1

• 1 other identifier: 15/0483
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 2

Brief Summary

Objectives: This is a feasibility study in preparation for the main multicentre randomised trial, which is anticipated to have two arms:

• Arm A: the current best standard of care \[rehabilitation exercises\]
• Arm B: the current best standard of care \[rehabilitation exercises\] + the experimental intervention In this feasibility trial the following aspects will be evaluated:
• Recruitment rates \[that is also willingness to be randomised\]
• Feasibility of providing the experimental intervention at the NHS study sites
• Retention rate/drop out rate
• Feasibility and acceptability of (i) proposed primary outcome \[patient-centred\], (ii) a range of additional patient-centred and clinician-centred outcomes
• Standard deviation of the proposed primary outcome so to inform sample size calculation of the main trial.
• Safety/toxicity of the study medication. Type of trial: Multicentre, parallel group, randomised controlled trial in 50 patients with radiotherapy-induced fibrosis of the head and neck. Trial design and methods: Participants over the age of 18, with radiotherapy-induced fibrosis of the head and neck will be given information about the trial and invited to participate. 50 participants who consent will be recruited and randomised to either:
• Treatment with pentoxifylline 400 mg tablets twice a day \[total 800mg/day\] + 500IU tocopherol acetate solution twice a day \[total 1000 IU/day\] in addition to best standard care \[a structured programme of rehabilitation exercises\] for 6 months or
• Best standard of care \[a structured programme of rehabilitation exercises\] for 6 months. Randomisation will be carried out online Trial duration per subject: 6 months Estimated total trial duration: 56 months Planned trial sites: Multi-site Total number of subjects planned: 50 participants Main inclusion/exclusion criteria: Inclusion Criteria:
• Subjects aged ≥18 years
• Previous history of Head \& Neck Cancer
• Previous radiotherapy to the Head \& Neck - minimum 50 Gy completed at least 12 months before screening visit
• Cancer-free for a minimum of 12 months after completion of radiotherapy.
• Diagnosis of radiotherapy-induced fibrosis of the head and neck: trismus and/or dysphagia
• Diagnosis of RIF of the head and neck by patient defined criteria:
• Trismus: "Does your mouth opening feel restricted?" Dysphagia: a score of 3 or more on the 10-item Eating Assessment Tool (EAT-10)29
• No history of primary cancer resection and/or reconstructive surgery to anatomical areas involved in swallowing and/or chewing with potential for altered and reconstructed muscular anatomy that may not be amenable to exercise/respond to antifibrotic medications (with the exception of diagnostic biopsy/tonsillectomy and neck dissections)
• Able to take study medications orally
• Subjects of child-bearing potential/potency must adhere to one method of highly effective contraception Exclusion Criteria:
• History of primary cancer resection and/or reconstructive surgery to anatomical areas involved in swallowing and/or chewing.
• Concomitant presence of other disorders that may cause pharyngeal/oral fibrosis
• Known hypersensitivity to pentoxifylline or tocopherol (vitamin E).
• History of acute porphyrias or haemorrhagic disorders
• Active/ongoing hypotension
• Diabetes
• Pregnancy
• Subjects with osteoradionecrosis
• Breastfeeding mothers
• Subjects with a MIO \<12mm
• Recurrent H\&N cancer or second primary H\&N cancer
• History of cerebral haemorrhage, extensive retinal haemorrhage or is at risk of increased bleeding (including those taking anticoagulants and platelet aggregation inhibitors)
• History of acute myocardial infarction, severe coronary artery disease, severe cardiac arrhythmias
• History of hepatic or renal impairment
• Expected non-compliance with treatment interventions or is considered unsuitable for trial participation at the discretion of the treating clinician
• Rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency Statistical methodology and analysis: Analysis of this feasibility trial will be mainly descriptive, measuring recruitment rate, acceptance of randomisation, attrition from treatment and trial, and completion rates for the outcome measures (to gauge acceptability and appropriateness).

Conditions

Head and Neck Fibrosis

Keywords

Head and Neck

Outcome Measures

Primary Outcomes (2)

• Feasibility assessed by recruitment rate and willingness to be randomised

  Feasibility will include recruitment rates/willingness to be randomised, which will be measured as a proportion of eligible subjects consenting to the trial.

  36 months

• Acceptability of the patient-centred primary outcome

  The acceptability of the patient-centred primary outcome (the EORTC QLQ-H\&N35 questionnaire, the proposed primary outcome measures of the future definitive trial) which will be measured as the proportion of randomised subjects with complete and useable data for all items of the EORTC QLQ-H\&N35 at the end of the study at 6 months .

  6 months

Secondary Outcomes (3)

• The feasibility and acceptability of a range of clinician-rated and patient-reported outcome measures.

  6 months

• Drop-out rate

  1, 3 and 6 months

• Safety/toxicity of the medication

  36 months

Other Outcomes (3)

• Assessment of trismus

  6 months

• Assessment of dysphagia

  6 months

• Estimates of standard deviation for the proposed primary outcome

  36 months

Study Arms (2)

Arm A

ACTIVE COMPARATOR

The current best standard of care \[rehabilitation exercises\]

Procedure: • Arm A: Best standard of care only [a structured programme of rehabilitation exercises] for 6 months

Arm B

EXPERIMENTAL

The current best standard of care \[rehabilitation exercises\] + the experimental intervention

Combination Product: Arm B: A combination of pentoxifylline and tocopherol acetate in addition to best standard care [a structured programme of rehabilitation exercises] for 6 months

Interventions

Arm B: A combination of pentoxifylline and tocopherol acetate in addition to best standard care [a structured programme of rehabilitation exercises] for 6 months COMBINATION_PRODUCT

• Arm B: A combination of pentoxifylline 800 mg/d in two 400-mg tablets and 1,000 IU/d of tocopherol acetate in two 500-IU aliquots in addition to best standard care \[a structured programme of rehabilitation exercises\] for 6 months

Arm B

• Arm A: Best standard of care only [a structured programme of rehabilitation exercises] for 6 months PROCEDURE

Prophylactic swallowing exercises consist of strap muscle exercises, airway protection exercises and base of tongue exercises

Arm A

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects aged ≥18 years at the time of signing the Informed Consent Form
• Subjects with diagnosis of radiotherapy-induced fibrosis of the head and neck: trismus and/or dysphagia as defined by the following patient-centred criteria: Trismus: "Does your mouth opening feel restricted" (answer must be yes). Dysphagia: a score of 3 or more on the 10-item Eating Assessment Tool (EAT-10)
• Previous History of Head \& Neck Cancer
• Previous radiotherapy to the Head \& Neck - minimum 50 Gy completed at least 12 months before screening visit
• No history of primary cancer resection and/or reconstructive surgery to anatomical areas involved in swallowing and/or chewing with potential for altered and reconstructed muscular anatomy that may not be amenable to exercise/respond to anti-fibrotic medications (with the exception of diagnostic biopsy/tonsillectomy and neck lymphadenectomy)
• Cancer-free for a minimum of 12 months after completion of radiotherapy, (complete clinical/radiological remission; absence of distant metastases)
• Able to understand the purpose of the study and willing to sign informed consent.
• Able to take study medications orally
• Subjects of child bearing potential/potency must adhere to one method of highly effective contraception.
• Subject has provided written informed consent
• Diagnosis of RIF of the head and neck by patient defined criteria:
• Trismus: "Does your mouth opening feel restricted?" Dysphagia: a score of 3 or more on the 10-item Eating Assessment Tool (EAT-10)29
• No history of primary cancer resection and/or reconstructive surgery to anatomical areas involved in swallowing and/or chewing with potential for altered and reconstructed muscular anatomy that may not be amenable to exercise/respond to antifibrotic medications (with the exception of diagnostic biopsy/tonsillectomy and neck dissections)
• Able to take study medications orally
• Subjects of child-bearing potential/potency must adhere to one method of highly effective contraception

You may not qualify if:

• Concomitant presence of other disorders that may cause trismus or dysphagia (e.g. active temporomandibular joint disorder limiting mouth opening, scleroderma, oral sub mucous fibrosis or other rheumatological or neurological disease)
• Subject has recurrent H\&N cancer or second primary H\&N cancer
• Subject has a known hypersensitivity to pentoxifylline or other xanthines such as caffeine, theophylline and theobromine or tocopherol (vitamin E).
• Subject has a history of acute porphyrias (acute intermittent porphyria, variegate porphyria, hereditary coproporphyria and 5-aminolaevulinic acid dehydratase deficiency porphyria)
• Subject has a history of cerebral haemorrhage, extensive retinal haemorrhage or is at risk of increased bleeding including those taking anticoagulants and platelet aggregation inhibitors such as: clopidogrel, eptifibatide, tirofiban, epoprostenol, iloprost, abciximab, anagrelide, NSAIDs other than selective COX-2 inhibitors, acetylsalicylates (ASA/LAS), ticlopidine, dipyridamole
• Subject has a history of acute myocardial infarction, coronary artery disease, cardiac arrhythmias
• Subject has a active/ongoing hypotension
• Subject has a active/ongoing hepatic or renal impairment
• Subject has a history of diabetes
• Expected non-compliance with treatment interventions or is considered unsuitable for trial participation at the discretion of the treating clinician.
• Current pregnancy as confirmed by urine pregnancy test at screening.
• Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency.
• Subjects with osteoradionecrosis of the jaw.
• Breastfeeding mothers
• Subjects with a MIO of \<12mm

Sponsors & Collaborators

• University College, London: lead
• National Institute for Health Research, United Kingdom: collaborator

Study Sites (2)

Aintree University Hospital NHS Foundation Trust

Liverpool, United Kingdom

Location

University College London Hospitals NHS Foundation Trust

London, United Kingdom

Location

MeSH Terms

Interventions

alpha-Tocopherol; WW Domain-Containing Oxidoreductase

Intervention Hierarchy (Ancestors)

Tocopherols; Vitamin E; Benzopyrans; Pyrans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Short Chain Dehydrogenase-Reductases; NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; Alcohol Oxidoreductases; Oxidoreductases; Enzymes; Enzymes and Coenzymes; Tumor Suppressor Proteins; Neoplasm Proteins; Proteins; Amino Acids, Peptides, and Proteins

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicentre, parallel group, randomised controlled trial in 50 patients with radiotherapy-induced fibrosis of the head and neck.

Study Record Dates

• First Submitted: October 24, 2018
• First Posted: October 29, 2018
• Study Start: September 1, 2019
• Primary Completion: December 31, 2021
• Study Completion: June 30, 2022
• Last Updated: March 3, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will not share

Locations

GB (2)