This study is a Phase 2, double-blind, randomized controlled trial evaluating the safety and efficacy of TV5M01 (a 5% green tea and 0.1% morphine gel) compared to triple mixture (0.19% lidocaine, 0.29% nystatin, and 5.50% hydroxides) for treating radiation-induced oral mucositis in patients with head and neck squamous cell carcinoma.

The trial will enroll 40 patients (20 per group) with stage III-IV head and neck cancer receiving radiotherapy who develop grade 1 or higher mucositis. Participants will apply the assigned mouthwash three times daily from mucositis diagnosis until resolution.

Primary outcomes include safety (incidence of infections and adverse events) and efficacy (duration of grade 3-4 mucositis, days with severe pain). Secondary outcomes include quality of life and analgesic use. Randomization will use minimization methodology to balance important prognostic factors.

The study design incorporates two interim analyses after 10 and 19 participants, with clear safety monitoring and stopping rules. If successful, this trial could provide an evidence-based treatment option for radiotherapy-induced mucositis, potentially improving treatment completion rates and quality of life for head and neck cancer patients.

Detailed Description

This Phase 2a randomized, double-blind controlled trial evaluates the efficacy and safety of TV5M01 (a 5% green tea extract and 0.1% morphine gel) for treatment of radiation-induced oral mucositis in head and neck cancer patients. Mucositis affects virtually all patients receiving radiotherapy for head and neck cancer, causing significant pain, impaired nutrition, and often necessitating treatment interruptions. Despite its prevalence, no effective evidence-based treatments exist.

The scientific rationale for TV5M01 combines two complementary mechanisms: the antioxidant and anti-inflammatory properties of green tea extract (epigallocatechin gallate) and the targeted analgesic effects of low-dose morphine. Preclinical studies demonstrate that EGCG inhibits radiation-induced cellular damage through multiple pathways, including reduction of reactive oxygen species, attenuation of pro-inflammatory cytokine expression, and mitigation of DNA damage. Topical morphine provides localized pain relief with minimal systemic absorption through peripheral opioid receptors that become upregulated in inflamed tissues.

This single-center trial will enroll 40 participants with stage III-IV squamous cell carcinoma of the head and neck who develop grade 1 or higher mucositis during radiotherapy. Participants will be randomized in a 1:1 ratio to receive either TV5M01 or triple mixture ("magic mouthwash" containing lidocaine, nystatin, and hydroxides) as 10mL oral rinses administered three times daily until mucositis resolution. The randomization employs a minimization algorithm to balance treatment groups across key prognostic factors including age, sex, tumor location, and histopathological grade.

To maintain blinding, both preparations will appear similar and will be dispensed in identical amber PET bottles. Stability studies confirm a 7-day shelf life when stored at 5°C. Comprehensive assessments include daily mucositis grading, pain scores, weekly oropharyngeal examinations with photographic documentation, and quality of life measures.

The trial incorporates robust safety monitoring with two planned interim analyses (after 13 and 26 participants). An independent Safety Monitoring Committee will review all adverse events and has authority to recommend early termination if safety concerns arise. Statistical analysis will employ non-parametric methods for efficacy comparisons, with sensitivity analyses using exact permutation techniques.

If successful, this trial could establish TV5M01 as an evidence-based treatment for radiation-induced mucositis, potentially improving treatment adherence and quality of life for head and neck cancer patients. The dual mechanism targeting both inflammation and pain represents an innovative approach to this challenging clinical problem that has remained largely unsolved despite decades of research.

A

y los subtitulos de imporancia Detailed Description Background and Significance

Head and neck squamous cell carcinoma represents a significant global health burden with increasing incidence in low and middle-income countries. Radiotherapy remains a cornerstone treatment modality, but oral mucositis develops in virtually 100% of patients receiving radiotherapy to the head and neck region. This complication frequently necessitates treatment modifications, potentially compromising oncologic outcomes and substantially impairing quality of life.

Despite its prevalence and clinical impact, current treatment options for radiation-induced mucositis remain suboptimal. The commonly used "magic mouthwash" preparations have demonstrated limited efficacy in controlled trials and face challenges with coverage of affected areas and patient-reported adverse effects.

Scientific Rationale

The TV5M01 formulation combines two active components with complementary mechanisms targeting the pathophysiology of radiation-induced mucositis:

The green tea extract (5%) contains epigallocatechin gallate (EGCG), which possesses potent antioxidant properties. In preclinical models, EGCG has demonstrated ability to inhibit radiation-induced apoptosis, reduce reactive oxygen species production, and attenuate pro-inflammatory pathways through NF-κB modulation.

The morphine component (0.1%) provides targeted analgesia through peripheral opioid receptors that become upregulated in inflamed tissues. The pharmacokinetic profile supports limited systemic absorption when applied topically, providing site-specific pain relief without significant central effects.

Study Design and Methodology

This trial employs a randomized, double-blind, controlled, parallel-group design to evaluate the superiority of TV5M01 compared to triple mixture. The study will enroll 40 participants allocated in a 1:1 ratio to either intervention or control groups.

Both preparations will be administered as 10mL oral rinses three times daily at 8-hour intervals, beginning upon diagnosis of grade 1 or higher mucositis and continuing until resolution or completion of radiotherapy.

Randomization and Blinding

The study utilizes a minimization randomization algorithm implemented through the REDCap platform to ensure balanced treatment groups across key prognostic factors including sex, age, tumor location, and histopathological grade.

To maintain blinding, both preparations will appear similar in color and consistency, will be dispensed in identical amber PET bottles, and will be labeled with participant identification codes only.

Monitoring and Safety Provisions

An independent Safety Monitoring Committee will oversee trial conduct and participant safety. Two formal interim analyses are planned after enrollment of 13 and 26 participants, respectively.

Pre-specified stopping rules include development of severe adverse events causally related to TV5M01, evidence of significant treatment inferiority at interim analyses, and regulatory safety alerts involving study components.

Anticipated Impact

If TV5M01 demonstrates superior efficacy compared to current standard approaches, it could significantly improve the management of radiation-induced mucositis, potentially enabling better adherence to planned radiotherapy regimens and enhancing quality of life during treatment. The dual-mechanism approach targeting both inflammatory processes and nociception represents an innovative strategy in addressing this challenging complication.

Inclusion Criteria:

Age ≥ 18 years and < 60 years

Diagnosis of HNSCC of the oral cavity, larynx, oro- and hypopharynx, diagnostic stage III-IV according to the AJCC 8th edition, scheduled to start radiotherapy

Ability to swallow solids and liquids before starting radiotherapy treatment

Adequate contraception for both sexes:

For women: negative pregnancy test for women of childbearing age; must be surgically sterile, postmenopausal (defined as absence of menstrual cycle for at least 12 consecutive months), or comply with an acceptable contraceptive regimen during and 3 months after the treatment period

For men: must be surgically sterile or comply with a contraceptive regimen during and for 3 months after the treatment period

Performance status (ECOG) of 0-1, measured within 72 hours prior to treatment initiation

Expected life expectancy ≥ 6 months

Adequate renal function [creatinine ≤ 1.5 times the upper limit of normal (ULN) or Glomerular Filtration Rate ≥ 50 ml/min]

Adequate liver function [total bilirubin ≤ 1.5 x ULN; AST or ALT ≤ 3 x ULN or ≤ 5 x ULN if due to tumor liver involvement]

Provision of signed and dated informed consent before initiating any study-related procedure

Meeting the diagnostic criteria for grade 1 or higher mucositis according to WHO classification

Meeting the criteria for starting radiotherapy

Willing and able to participate in the trial and comply with all trial requirements

Exclusion Criteria:

Patients not eligible for radiotherapy

Stomatological disease such as ulcers, edema, exudation in the oropharyngeal mucosa before radiotherapy

Women who are pregnant or breastfeeding

Patients allergic or sensitive to any of the compounds in the gel or study medications

Presence of lesions that completely occlude the upper digestive tract

Patients with a history of disorders, specifically those with psychotic psychiatric disorders such as schizophrenia, schizoaffective disorder, and delusional disorder, and substance/alcohol abuse

Patients participating or who have participated in another clinical trial in the last 30 days

Another uncontrollable, severe, hemodynamically unstable concurrent medical condition requiring urgent attention or threatening the patient's life

Receiving chemotherapy regimens with delayed toxicity within the last 4 weeks (six weeks for nitrosourea or mitomycin C) or continuous or weekly chemotherapy regimen with limited potential for delayed toxicity within the last two weeks

Any evidence of oral infection or disease in the oral cavity other than HNSCC

Any important medical disease or incidental abnormal laboratory finding that could increase the participant's risk in the study (based on the investigator's judgment)

Concomitant therapy with drugs that inhibit or enhance opioid action

Hypersensitivity to opioids, respiratory depression, obstructive airway disease, acute liver disease, seizure disorder, increased intracranial pressure, paralytic ileus, patients with known sensitivity to morphine, pheochromocytoma, acute asthma exacerbations, history of cardiac arrhythmia, heart failure.

Data publication policy: Our identifiable personal data (IPD) is not publicly available to protect participant privacy and confidentiality. We do not plan to share individual participant data with external researchers due to: 1) local regulatory restrictions, 2) the sensitive nature of the medical information collected, 3) limitations in our institutional data sharing infrastructure, and 4) commitments made to participants during the informed consent process regarding data confidentiality. Our ethics committee has approved this data management approach in accordance with Colombian regulations.