Effect of N-Acetyl Cysteine (NAC) on the Oral Microbiome

Study Overview
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Brief Summary
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This is a Phase II treatment, randomized 3:1 ratio, open label clinical trial to study the effect of short duration administration of N-acetyl cysteine on oral microbiome and on mucositis caused by concurrent chemotherapy and radiotherapy.

Detailed Description
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Primary Objective(s) I. To determine whether short duration pre-treatment with N-acetyl cysteine reduces the rate of severe mucositis that develops during the standard concurrent chemoradiotherapy in patients with locally advanced Head and Neck Squamous Cell Cancer. Secondary Objective(s) I. Identify the effect of N-acetyl cysteine on the oral microbiome. II. Identify the effect of short duration pre-treatment with N-acetyl cysteine on the duration and delay onset of severe radiation-induced mucositis developed during the standard concurrent chemoradiotherapy in patients with locally advanced Head and Neck Squamous Cell Cancer. III. Bank saliva and blood for future studies of biomarkers that will be correlated with changes in the oral microbiome and the duration of mucositis. IV. Determine if there is any effect of short duration pre-treatment with N-acetyl cysteine on tumor response to standard CRT as measured within the first year of treatment. V. Determine the relationship between human papillomavirus status and smoking status and the baseline microbiome as well as well as the possible differential effect of N-acetyl cysteine on the structure of the oral microbiome in human papillomavirus positive patients vs smokers. VI. Gather data on the incidence, severity, duration and onset of severe radiation-induced mucositis as well as data on saliva and blood biomarkers and evaluation of the oral microbiome in patients receiving standard of care primary or adjuvant chemoradiotherapy to gather preliminary data for use in designing future Phase 3 studies.

Official Title
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Effect of N-Acetyl Cysteine (NAC) on the Oral Microbiome and on the Degree of Mucositis Developed in Response to Concurrent Chemotherapy and Radiotherapy in Patients With Locally Advanced Squamous Cell Carcinoma of the Head and Neck

Conditions
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Head and Neck Cancer

Intervention / Treatment
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* Drug: N-Acetyl-L-Cysteine dietary supplement
* Radiation: Chemotherapy and Radiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have histologically or cytologically confirmed HNSCC. Patients must be scheduled for definitive or adjuvant concurrent drug therapy and radiotherapy to include the oral cavity in the field and have a window of at least 14 days between the treatment decision and beginning of treatment. Patients must be ≥ 18 years old. Willing to provide consent for collection of samples of blood and saliva as scheduled through the treatment. Subject is willing and able to comply with the protocol for the duration of the study. Ability to understand and the willingness to sign an IRB-approved informed consent document. Exclusion Criteria: Patients who have used NAC as a supplement or as a treatment within the last 6 months. Patients who have participated in another clinical study with an investigational product during the last 8 weeks. Receipt of anti-cancer therapy (chemotherapy, immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal antibodies, other investigational agent) within the last 8 weeks. Patients who are unable to swallow pills. Patients Patient is on medications that need to be continued and that might interact with NAC. Uncontrolled pre-existent illness of the digestive tract such as PUD, GERD. Any condition that, in the opinion of the investigator, would interfere with evaluation of study treatment or interpretation of patient safety or study results

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nature's Blend N-Acetyl-L-Cysteine 600 mg with Chemotherapy<br>The treatment with NAC will be given twice daily for at least 10 days with the goal to cover the window of opportunity time between the treatment decision for CRT and the beginning of treatment (usually 14-21 days). | Drug: N-Acetyl-L-Cysteine dietary supplement<br>* Treatment will be administered on an outpatient basis, either twice daily or 48 hours prior to starting chemotherapy radiation. Eligible participants will start NAC at least 9 days before definitive or adjuvant radiation therapy.<br>* Other names: N-Acetyl-L-Cysteine;Radiation: Chemotherapy and Radiation<br>* Participants will receive definitive or adjuvant concurrent chemotherapy and radiotherapy s per standard of care.<br>|
| Other: Standard of Care Chemotherapy (CONTROL)<br>Patients will receive definitive or adjuvant concurrent chemotherapy and radiotherapy as per standard of care | Radiation: Chemotherapy and Radiation<br>* Participants will receive definitive or adjuvant concurrent chemotherapy and radiotherapy s per standard of care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Reduction in Severe Mucositis with Pre-treatment N-acetyl cysteine | Severe mucositis will be defined as Grade III or IV mucositis as per WHO OM classification. | 3 months post treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Effects of N-acetyl cysteine on oral microbiome | Oral microbiome profiling will be determined using 16S rRNA gene sequencing to characterize the bacterial diversity and composition in the saliva collected from participants before and after treatment. | At baseline and one year post treatment | 
| Effects of standard of care chemoradiotherapy on oral microbiome | Oral microbiome profiling will be determined using 16S rRNA gene sequencing to characterize the bacterial diversity and composition in the saliva collected from participants before and after treatment. | At baseline and one year post treatment | 
| Number of Incidences of Severe Mucositis on N-acetyl cysteine | Time of development of mucositis grade III or above (marked as treatment day) and time of resolution below grade III (marked as post-treatment day) will be recorded and will serve to measure duration and delay onset of severe mucositis. For the time to event data, Kaplan Meier curves will be constructed to determine the median time to occurrence of severe mucositis. | One year post treatment | 
| Number of Incidences of Severe Mucositis with Standard of Care Chemoradiotherapy | Time of development of mucositis grade III or above (marked as treatment day) and time of resolution below grade III (marked as post-treatment day) will be recorded and will serve to measure duration and delay onset of severe mucositis | One year post treatment | 
| Number of Participants with Change in Saliva Biomarkers - N-acetyl cysteine | Banked saliva to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of saliva. | At baseline and one year post treatment | 
| Number of Participants with Change in Saliva Biomarkers - Standard of Care Chemoradiotherapy | Banked saliva to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of saliva. | At baseline and one year post treatment | 
| Number of Participants with Change in Blood Biomarkers - N-acetyl cysteine | Blood samples to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of blood. | At baseline and one year post treatment | 
| Number of Participants with Change in Blood Biomarkers - Standard of Care Chemoradiotherapy | Blood samples to describe biomarkers that could correlate with oral microbiome changes and with the severity of mucositis. Measurements that would be considered are evaluations of the nitrate reducing and NO producing capacity of oral bacteria, saliva H2S measurements and metabolic profiling of blood. | At baseline and one year post treatment | 
| Tumor Response | Results of standard imaging studies and tumor response or progression will be collected from participant's electronic medical record and compared between participants pre-treated with N-acetyl cysteine and those no treated with N-acetyl cysteine. | One year post treatment | 
| Probability in Structure Changes of Microbiomes in Relation to Human Papillomavirus and Smoking Statuses and N-acetyl cysteine | Human papillomavirus status and smoking status at baseline will be examined and microbiome data collected over time will be compared between each group (i.e. smokers vs non-smokers) and (HPV+ vs HPV-) and then with both groups combined (smoker/HPV+, smoker/HPV-, non-smoker/HPV+ and non-smoker/HPV-) for continuous measures that describe the microbiome measures, a repeated measures mixed model will be used to make these comparisons where participants will be considered as random effects and HPV status, smoking status and time (and their interactions) will be considered as fixed effects. | One year post treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Head and neck squamous cell cancer