Efficacy and Safety Study of Clonidine Lauriad® to Treat Oral Mucositis

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the efficacy and safety of Clonidine Lauriad® to treat chemoradiation therapy induced severe oral mucositis in patients with head and neck cancer.

Official Title
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A Phase II, Multi-center, Randomised, Double-blind, Placebo-controlled Study Comparing the Efficacy and Safety of Clonidine Lauriad® 50 μg and 100 μg Mucoadhesive Buccal Tablet (MBT) Applied Once Daily to Those of Placebo in the Prevention and Treatment of Chemoradiation Therapy Induced Oral Mucositis in Patients With Head and Neck Cancer

Conditions
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Oral Mucositis

Intervention / Treatment
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* Drug: Clonidine Lauriad® 50µg
* Drug: Clonidine Lauriad® 100µg
* Drug: Placebo Lauriad®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female Aged > 18 years Suffering from a newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx histologically-confirmed and having undergone resective surgery Prior neoadjuvant chemotherapy allowed provided that, the patient did not experience a World Health Organization (WHO) grade > 2 oral mucositis during the neoadjuvant therapy. Patient eligible to receive concurrent chemo-radiation defined as: A continuous course of conventional external beam irradiation (IMRT eligible) with a minimum cumulative radiation dose of 50 Gy or a maximum of 70 Gy, based on a daily dosing between 1.8 and 2.2 Gy combined with platinum based chemotherapy on a weekly or tri-weekly cycles. Planned radiation treatment fields must include at least two oral tissue sites (among right or left buccal mucosa, floor of mouth, tongue, right or left soft palate) with each site receiving a total of 50 Gy or a maximum of 70 Gy. The radiation treatment plan will be reviewed by a designated radiation oncologist. Eastern Cooperative Oncology Group (ECOG) performance status ≤2 Screening laboratory tests: Haemoglobin ≥ 10g/dL Absolute neutrophil counts ≥ 1500 cells/mm3 Platelets ≥ 100.000/mm3 Conjugated bilirubin ≤ 2 times Upper Limit of Normal (ULN) Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN Negative serum pregnancy test Women of child bearing potential must have effective contraception method (oral or device) Signed written informed consent Exclusion Criteria: Tumours of the lips, sinuses, salivary glands Prior radiation of the head and neck area Curative surgery less than 2 weeks or more than 15 weeks prior to the initiation of radiation therapy-chemotherapy (RT-CT) Presence of active infectious disease Presence of active oral infectious disease, including oropharyngeal candidiasis and/or orofacial herpes Presence of oral mucositis Known or suspected chronic viral diseases including HIV Systolic blood pressure < 100 mmHg and/or Diastolic blood pressure < 50 mmHg Recent stroke within the last 6 months Bradyarrhythmia (<60 b/min), including sinus node dysfunction or atrioventricular (AV) nodal conduction block 2nd or 3rd degree Subjects with orthostatic hypotension, defined by a decrease of systolic BP and/or diastolic BP above 20 mmHg when the patient stands up Renal insufficiency (creatinine blood level > 1.5ULN) Ongoing heavy alcohol consumption (>100g alcohol/day) Administration of any concomitant treatment likely to interfere with clonidine Known hypersensitivity to clonidine, history of allergy or intolerance to milk proteins or any other component of the product Presence of severe or uncontrolled depression Pregnant or breast-feeding women Inability to give informed consent or comply with study requirements Unable or unwilling to comply with follow-up visits Participation to a clinical trial within 30 days prior to randomization and during the entire duration of the study

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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Clonidine Lauriad® 50µg<br>50µg muco-adhesive buccal tablets, once de day, every day up to 8 weeks | Drug: Clonidine Lauriad® 50µg<br>* 50µg muco-adhesive buccal tablet once day every day up to 8 weeks<br>|
| Active Comparator: Clonidine Lauriad® 100µg<br>100µg muco-adhesive buccal tablets, once a day, every day up to 8 weeks | Drug: Clonidine Lauriad® 100µg<br>* 100µg muco-adhesive buccal tablets, once a day, every day up to 8 weeks<br>|
| Placebo Comparator: Placebo Lauriad®<br>Placebo muco-adhesive buccal tablets, once a day, every day up to 8 weeks | Drug: Placebo Lauriad®<br>* placebo muco-adhesive buccal tablets, once a day, every day up to 8 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cumulative Radiation Dose at Which Severe Oral Mucositis (World Health Organization [WHO] Score ≥ 3) Was First Observed | The primary endpoint planned in the protocol was the percentage of participants with an oral mucositis score greater than or equal to 3 using the WHO oral mucositis severity scale at a cumulative radiation dose of 50 Gy. This was modified by protocol amendment to the cumulative radiation dose at which a WHO score greater than or equal to 3 was first observed. This change was made to account for the fact that in real practice most patients receive a cumulative dose between 60 and 70 Gy. The presence of grade 3 or 4 oral mucositis was assessed twice weekly during the active phase (radiotherapy) by a trained radiation oncologist or an ear nose and throat specialist who took into account the field of radiation treatment. WHO score 3 = oral ulcers, liquid diet only; WHO score 4 = oral alimentation impossible. Each assessment was associated with the actual cumulative dose of radiotherapy. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| At Least One Opioid Use (Class 3 Analgesic) | Opioid use was recorded twice weekly during the active phase (radiotherapy) | 8 weeks | 
| Opioid Use: Minimal Total Cumulative Dose Administered (Mean, Standard Deviation) | Opioid use was recorded twice weekly for up to 8 weeks during the active phase (radiotherapy). The sum of non-missing total cumulative doses across all class 3 analgesics recorded for the considered participant is reported. | 8 weeks | 
| Opioid Use: Minimal Total Cumulative Dose Administered (Median, Range) | Opioid use was recorded twice weekly for up to 8 weeks during the active phase (radiotherapy). The sum of non-missing total cumulative doses across all class 3 analgesics recorded for the considered participant is reported. | 8 weeks | 
| Overall Survival | After the end-of study visit, the investigator center collects OS follow-up data for each patient who has consented to participate in the follow-up data collection. the OS follow-up period was still ongoing at time of the primary analysis and ended in Nov 2016. The analysis was condicted on the ITT population. The overall survival was evaluate every 6 months after last subject completed in patients who has consented to participate . | 2 years |