Effect of Arginine and Glutamine Oral Suspension on EGF in Radiation Induced Oral Mucositis: A Trible Blinded Randomized Controlled Clinical Trial

Phase 2

Active, not recruiting

• Conditions: Radiation Induced Oral Mucositis; Oral Mucositis Due to Radiation; Oral Mucositis

• Registration Number: NCT07020754
• Lead Sponsor: Ain Shams University

Brief Summary

This triple-blinded, randomized controlled clinical trial investigates the effectiveness of L-arginine and L-glutamine oral suspensions in managing radiation-induced oral mucositis (RIOM) in patients with head and neck cancer (HNC) undergoing radiotherapy. A total of 69 patients are randomly assigned to three groups: L-arginine + maltodextrin, glutamine + maltodextrin, or maltodextrin alone (control).

The interventions are administered as a swish-and-swallow solution three times daily from the second to seventh week of radiotherapy. Key outcomes assessed include oral mucositis severity (WHO scale), pain intensity (VAS), body mass index (BMI), oral health-related quality of life (OHIP-14), and salivary epidermal growth factor (EGF) levels. The study aims to determine whether L-arginine offers superior mucosal healing and symptom relief compared to glutamine or placebo.

Detailed Description

Radiation-induced oral mucositis (RIOM) is recognized as a frequent and severe complication among patients with head and neck cancer (HNC) who undergo radiotherapy (RT) 1. It manifests as damage to healthy tissues, specifically inflammation and/or ulceration of the oral mucosa, affecting over 80% of these patients receiving radiation therapy 2.

RIOM manifests as a normal tissue injury lasting from 7 to 98 days, initiated by acute inflammation in the oral mucosa, tongue, and pharynx following RT exposure 1. This inflammation is accompanied by the accumulation of various inflammatory cells and the secretion of cytokines, chemotactic agents, and growth factors. RIOM may escalate into a life-threatening condition due to significant blockages that restrict the intake of food and water, leading to weight loss and septic issues from the loss of protective epithelial and basement membrane layers. Consequently, these complications can disrupt cancer treatment and necessitate changes in the radiation dose, thus impacting local tumor control.3 The pathogenesis of RIOM associated with RT for HNC unfolds through a complex, multi-stage process. Initially, ionizing radiation directly damages cellular DNA within the radiation field, resulting in lethal double-strand breaks. When these breaks are not repaired accurately, it leads to programmed cell death or apoptosis. Concurrently, this radiation exposure stimulates various cells such as endothelial cells and fibroblasts to produce reactive oxygen species (ROS). These ROS further exacerbate DNA damage and disrupt cellular functions by modifying protein and lipid membrane structures, leading to escalated inflammation 4.

When excessive ROS accumulate, they cause oxidative stress, managed by antioxidants like superoxide dismutase and glutathione peroxidase. Disruptions in this balance lead to oxidative damage, increasing the risk of cancer and inflammatory conditions. Chemoradiation activates NF-kappa B, heightening pro-inflammatory cytokine levels that drive the progression to mucosal ulceration characteristic of OM. This condition severely impacts patients' nutrition and oral hygiene and increases the risk of secondary infections due to deeper tissue damage 5.

L- glutamine is L-alpha-amino acid. It is the most abundant free amino acid in human blood. L- glutamine is needed for several functions in the body including for the synthesis of proteins as well as an energy source. L-glutamine can be synthesized by the body and can also be obtained from the diet if needed.6 L- glutamine is crucial for powering lymphocytes and the gastrointestinal tract, helping to protect against infections and maintaining the mucosal barrier. It's important in cellular metabolism and acts as a nitrogen carrier across various tissues. Although its plasma levels remain stable, glutamine is predominantly stored in muscles and regulated by the liver 7. Several studies indicated that glutamine could decrease both the frequency and intensity of OM 8-13.

L-arginine, a conditionally essential amino acid, is primarily metabolized by enzymes such as nitric oxide synthase (NOS), arginine decarboxylase, and arginase (ARG), contributing to the synthesis of proteins and various bioactive molecules like nitric oxide (NO), proline, creatine, and polyamines 14. There is growing interest in enhancing the physiological roles of arginine, particularly in reducing intestinal inflammation and oxidative stress 15. Previous research has shown that L-arginine supplementation in both animals and humans with intestinal disorders can lessen intestinal damage, alleviate oxidative stress and inflammation, and help reestablish mucosal immune balance. Notably, Coburn et al. have documented that L-arginine supplementation reduced intestinal inflammation in mouse models of dextran sulfate sodium (DSS)- induced colitis, an experimental model of IBD.16 L-arginine significantly enhances wound healing through various mechanisms. It is crucial for collagen synthesis, which is fundamental for new tissue development and the formation of strong connective tissue. This amino acid also has anti-inflammatory effects that regulate the body's response to injury, reducing the risk of chronic inflammation that can impede healing. Additionally, l-arginine promotes fibroblast proliferation, which is essential for producing collagen and other extracellular matrix components that aid in wound repair. Indirect benefits of l-arginine include improved circulation and blood flow to the wound area, supplying necessary oxygen and nutrients, and bolstering the immune system to fight infections and support healing processes 17-20.

Based on the various physiological properties of L-arginine, its anti-inflammatory effects, and its capacity for wound healing and tissue repair, this study aim to evaluate the effect of L-arginine oral suspension versus glutamine oral suspension on salivary EGF, and on management of radiation-induced oral mucositis (RIOM) and its associated symptoms, as well as assessing their effects on the oral health related quality of life in HNC patients.

Study Timeline

• Study Start: 2025-04-01
• Status Verified: 2025-06
• Study First Submitted: 2025-06-06
• Study First Submitted QC: 2025-06-06
• Last Update Submitted: 2025-06-06
• Study First Posted: 2025-06-13
• Last Update Posted: 2025-06-13
• Primary Completion: 2025-06-15
• Study Completion: 2025-07-01

Recruitment & Eligibility

• Status: ACTIVE_NOT_RECRUITING
• Sex: All
• Target Recruitment: 69

Inclusion Criteria

• Age between 20 and 70 years

Diagnosed with head and neck cancer (HNC) and undergoing radiotherapy (RT)

Development of oral mucositis during the 2nd to 3rd week of RT

Receiving a minimum radiation dose of 50 Gy to the oral cavity

Undergoing intensity-modulated radiotherapy (IMRT) with three-dimensional conformal techniques after complete tumor resection

Ability and willingness to provide informed consent

Able to comply with study procedures and follow-up assessments

Exclusion Criteria

• History of prior radiotherapy

Diagnosed with diabetes mellitus

Presence of salivary gland tumors

Renal or hepatic insufficiency

Sepsis or any active systemic infection

Distant metastases

Any condition that may interfere with oral sample collection or affect EGF levels (e.g., autoimmune oral disease)

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Primary Outcome Measures

Name	Time	Method
Change in Salivary Epidermal Growth Factor (EGF) Levels	Baseline (2nd week of radiotherapy) End of treatment (7th week)	Description: Measures the concentration of salivary EGF, a key biomarker involved in mucosal healing and epithelial regeneration. This outcome assesses whether L-arginine or L-glutamine can enhance EGF production, contributing to faster recovery from oral mucositis.; Method: Whole saliva is collected under stimulation, processed, and analyzed using ELISA (Enzyme-Linked Immunosorbent Assay).

Secondary Outcome Measures

Name	Time	Method
Severity of Oral Mucositis	2nd, 5th, and 7th weeks of radiotherapy	Assessed using the WHO Oral Toxicity Scale, which grades mucositis from 0 (no symptoms) to 4 (severe ulceration requiring feeding support). This measure reflects the extent of mucosal injury caused by radiotherapy and the potential protective effect of interventions.
Pain Intensity	2nd, 5th, and 7th weeks of radiotherapy	Evaluated using the Visual Analogue Scale (VAS) ranging from 0 (no pain) to 10 (worst imaginable pain). This subjective measure tracks changes in patient-reported pain severity throughout treatment.
Effectiveness Index (EI)	2nd, 5th, and 7th weeks of radiotherapy	Description: A calculated index that quantifies symptom improvement based on both WHO mucositis grades and VAS pain scores. It categorizes treatment response into four levels: No improvement (\<30%); Moderate improvement (30%-70%); Marked improvement (70%-95%); Healed (≥95%)
Oral Health-Related Quality of Life (OHIP-14)	2nd, 5th, and 7th weeks of radiotherapy	Evaluates the functional and psychological impact of oral mucositis on daily life using the validated Oral Health Impact Profile-14 questionnaire. It covers domains such as functional limitation, physical pain, psychological discomfort, and social disability.; Scoring: 0-56, with lower scores indicating better quality of life

Trial Locations

Locations (1)

Faculty of Dentistry, Future University in Egypt; 🇪🇬 Cairo, Egypt