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

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

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.

Study Overview

• Status: Completed
• Conditions: Oral Mucositis
• Intervention / Treatment: Drug: Clonidine Lauriad® 50µg; Drug: Clonidine Lauriad® 100µg; Drug: Placebo Lauriad®

• Study Type: Interventional
• Enrollment (Actual): 183
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Besançon, France, 25030
    • Hospital Jean Minjoz
  • Brest, France, 29000
    • CHU Morvan
  • Caen, France, 14000
    • Centre François Baclesse
  • Evreux, France, 27000
    • Clinique Pasteur
  • Lille, France, 59000
    • Centre Oscar Lambret
  • Limoges, France, 87000
    • Clinique Chenieux
  • Neuilly-sur-Seine, France, 92200
    • Clinique Hartmann
  • Pierre-Bénite, France, 69495
    • CH Lyon sud
  • Poitiers, France, 86000
    • CHU La Miletrie
  • Saint gregoire, France, 35760
    • CHP St Grégoire
  • Saint-Nazaire, France, 44600
    • Centre de Cancérologie Etienne-Dolet
  • Tours, France, 37000
    • Hôpital Bretonneau
  • Villejuif, France, 94805
    • Institut Gustave Roussy
• Germany
  • Erlangen, Germany, 91054
    • Universitatsklinikum Erlangen Strahlenklinik
  • Essen, Germany, 45147
    • Universitätsklinikum Essen
  • Freiburg, Germany, 79106
    • Universitatsklinikum Freiburg Klinik fur Strahlentherapie
  • Leipzig, Germany, 04103
    • Universitatsklinikum Leipzig
  • Osnabruck, Germany, 49076
    • Paracelsius- Klinik
• Hungary
  • Nyíri u. 38
    • Kecskemét, Nyíri u. 38, Hungary, 6000
      • Bacs-Kiskun Megyei Korhaz Szegedi Tudomanyegyetem Altalanos Orvostudomanyi Kar Oktato Korhaza
  • Szent István út 68
    • Nyíregyháza, Szent István út 68, Hungary, 4400
      • Jósa András Oktatókórház Egészségügyi Szolgáltató Nonprofit Kft.
  • Szentpéteri kapu 72-76
    • Miskolc,, Szentpéteri kapu 72-76, Hungary, 3526
      • Borsod-Abauj-Zemplen Megyei Korhaz es Egyetemi Oktato Korhaz
  • Tétényi út 12-16.
    • Budapest, Tétényi út 12-16., Hungary, 1115
      • Szent Imre Kórház
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28006
    • Hospital Universitario de La Princesa
  • Madrid, Spain, 28041
    • Hospital 12 de Octubre
  • Madrid, Spain
    • Hospital Universitario Ramón y Cajal
  • Madrid, Spain, 28222
    • Hospital Puerta de Hierro Majadahonda
  • Malaga, Spain, 29010
    • Hospital Virgen de la Victoria
  • Malaga, Spain, 29010
    • Hospital Carlos Haya
  • Pamplona, Spain
    • Hospital De Navarra
• Switzerland
  • Lausanne, Switzerland, 1011
    • Centre Hospitalier Universitaire
• United States
  • Arizona
    • Sun City, Arizona, United States, 85251
      • 21st Century Oncology of Arizona
  • California
    • Corona, California, United States, 92879
      • Compassionate Cancer Care Medical Group
    • Duarte, California, United States, 91010
      • City of Hope
    • Fresno, California, United States, 93720
      • California Cancer Associates for Researche and Excellence
    • Riverside, California, United States, 92501
      • Compassionate Cancer Care Medical Group
    • Santa Maria, California, United States, 93454
      • Central Coast Medical Oncology Corp.
  • Colorado
    • Denver, Colorado, United States, 80210
      • Centura Health Research Center
  • Connecticut
    • Farmington, Connecticut, United States, 06030
      • University of Connectcut Health Center
  • Florida
    • Miami, Florida, United States, 33145
      • AMPM Research Clinic
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Barbara Ann Karmonos Cancer Hospital
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of medecine
  • Montana
    • Billings, Montana, United States, 59101
      • Billings Clinic Montana
  • New York
    • Mineola, New York, United States, 11501
      • Winthrop University Hospital
    • The Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28203
      • Carolinas Medical Center- Carolinas Health Care System
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Penn State Hershey Cancer Institut
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Vanderbilt Ingram Cancer Center
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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:

  1. 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.
  2. 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:

  1. Haemoglobin ≥ 10g/dL
  2. Absolute neutrophil counts ≥ 1500 cells/mm3
  3. Platelets ≥ 100.000/mm3
  4. Conjugated bilirubin ≤ 2 times Upper Limit of Normal (ULN)
  5. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 ULN
  6. 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: TRIPLE

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Clonidine Lauriad® 50µg; 50µg muco-adhesive buccal tablets, once de day, every day up to 8 weeks	Drug: Clonidine Lauriad® 50µg; 50µg muco-adhesive buccal tablet once day every day up to 8 weeks
ACTIVE_COMPARATOR: Clonidine Lauriad® 100µg; 100µg muco-adhesive buccal tablets, once a day, every day up to 8 weeks	Drug: Clonidine Lauriad® 100µg; 100µg muco-adhesive buccal tablets, once a day, every day up to 8 weeks
PLACEBO_COMPARATOR: Placebo Lauriad®; Placebo muco-adhesive buccal tablets, once a day, every day up to 8 weeks	Drug: Placebo Lauriad®; placebo muco-adhesive buccal tablets, once a day, every day up to 8 weeks

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Onset of Severe Oral Mucositis	Time to onset is the duration until first Severe Oral Mucositis. Severe Oral Mucositis was defined as a Grade 3 or Grade 4 score on the World Health Organization (WHO) oral mucositis severity scale. Participants were 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 = ulcers, extensive erythema, and the inability of the participant to swallow a solid diet; WHO score 4 = mucositis to the extent that alimentation was not possible.	8 weeks
The Maximum Severity of Oral Mucositis	Participants were assessed using the World Health Organization (WHO) oral mucositis severity scale 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. The WHO scores were as follows: 0 = None; 1 = oral soreness, erythema; 2 = oral erythema, ulcers, solid diet tolerated; 3 = oral ulcers, liquid diet only; 4 = oral alimentation impossible. The maximum severity was the maximum score reported during the active phase.	8 weeks
The Overall Incidence of Grade 3/4 Mucositis During the Active Phase.	The presence of grade 3 or 4 oral mucositis on the World Health Organization (WHO) oral mucositis severity scale 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 = ulcers, extensive erythema, and the inability of the participant to swallow a solid diet; WHO score 4 = mucositis to the extent that alimentation was not possible.The number of participants with at least one Grade 3 or Grade 4 mucositis score during the active phase is reported.	8 weeks
Salivary Flow Assessment Using the National Cancer Institute-Common Terminology Criteria (NCI-CTC) for Xerostomia: Time to First Grade 2 or Higher	Salivary flow was assessed and scored by the investigator weekly using the NCI-CTC scale for xerostomia for up to 8 weeks during the active phase (radiotherapy). Time to appearance of Grade 2 or higher on the following 4-point scoring scale is reported: 0 = normal; 1 = symptomatic (dry or thick saliva) without significant dietary alteration (unstimulated saliva flow greater than 0.2 mL/minute); 2 = symptomatic and significant oral intake alterations (e.g. copious water, other lubricants, diet limited to purees and/or soft, moist foods) (unstimulated saliva 0.1 to 0.2 mL/minute); and 3 = symptoms leading to inability to adequately aliment orally, intravenous fluids, tube feedings, or total parenteral nutrition indicated (unstimulated saliva < 0.1 mL/minute).	8 weeks
Overall Treatment Compliance According to the Patient Diary	All participants complete a daily questionnaire during the active phase (radiotherapy). Compliance = [ number of tablets / (end date of treatment - start date treatment + 1 ) ] * 100. The "number of tablets" is the number of days with a tablet applied and treatment start and end dates are the first and last dates of the patient diary with a tablet applied.	8 weeks

Collaborators and Investigators

• Sponsor: Onxeo
• Investigators: Study Director: Bérangère Vasseur, MD, Onxeo

Study record dates

Study Major Dates

• Study Start: April 1, 2010
• Primary Completion (ACTUAL): October 1, 2014
• Study Completion (ACTUAL): December 1, 2014

Study Registration Dates

• First Submitted: June 29, 2011
• First Submitted That Met QC Criteria: June 29, 2011
• First Posted (ESTIMATE): June 30, 2011

Study Record Updates

• Last Update Posted (ACTUAL): November 28, 2017
• Last Update Submitted That Met QC Criteria: October 23, 2017
• Last Verified: October 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Gastrointestinal Diseases; Gastroenteritis; Stomatognathic Diseases; Mouth Diseases; Mucositis; Stomatitis; Physiological Effects of Drugs; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Analgesics; Sensory System Agents; Adrenergic alpha-2 Receptor Agonists; Adrenergic alpha-Agonists; Adrenergic Agonists; Sympatholytics; Clonidine
• Other Study ID Numbers: BA2009/28/01