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

Oral Mucositis Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01385748
• Other study ID #: BA2009/28/01
• Status: Completed
• Phase: Phase 2
• First received: June 29, 2011
• Last updated: October 23, 2017
• Start date: April 2010
• Est. completion date: December 2014

Study information

• Verified date: October 2017
• Source: Onxeo
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 183
• Est. completion date: December 2014
• Est. primary completion date: October 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Mucositis
• Oral Mucositis
• Stomatitis

Intervention

Drug:
• Clonidine Lauriad® 50µg
50µg muco-adhesive buccal tablet once day every day up to 8 weeks
• Clonidine Lauriad® 100µg
100µg muco-adhesive buccal tablets, once a day, every day up to 8 weeks
• Placebo Lauriad®
placebo muco-adhesive buccal tablets, once a day, every day up to 8 weeks

Locations

Country	Name	City	State
France	Hospital Jean Minjoz	Besançon
France	CHU Morvan	Brest
France	Centre François Baclesse	Caen
France	Clinique Pasteur	Evreux
France	Centre Oscar Lambret	Lille
France	Clinique Chénieux	Limoges
France	Clinique Hartmann	Neuilly-sur-Seine
France	CH Lyon Sud	Pierre-Bénite
France	CHU La Milétrie	Poitiers
France	CHP St gregoire	Saint gregoire
France	Centre de Cancérologie Etienne-Dolet	Saint-Nazaire
France	Hôpital Bretonneau	Tours
France	Institut Gustave Roussy	Villejuif
Germany	Universitatsklinikum Erlangen Strahlenklinik	Erlangen
Germany	Universitatsklinikum Essen	Essen
Germany	Universitatsklinikum Freiburg Klinik fur Strahlentherapie	Freiburg
Germany	Universitatsklinikum Leipzig	Leipzig
Germany	Paracelsius- Klinik	Osnabruck
Hungary	Szent Imre Kórház	Budapest	Tétényi út 12-16.
Hungary	Bács-Kiskun Megyei Kórház Szegedi Tudományegyetem Általános Orvostudományi Kar Oktató Kórháza	Kecskemét	Nyíri u. 38
Hungary	Borsod-Abaúj-Zemplén Megyei Kórház és Egyetemi Oktató Kórház	Miskolc,	Szentpéteri kapu 72-76
Hungary	Jósa András Oktatókórház Egészségügyi Szolgáltató Nonprofit Kft.	Nyíregyháza	Szent István út 68
Spain	Hospital Vall d'Hebron	Barcelona
Spain	Hospital 12 de octubre	Madrid
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Puerta de Hierro Majadahonda	Madrid
Spain	Hospital Universitario de La princesa	Madrid
Spain	Hospital Universitario Ramon y cajal	Madrid
Spain	Hospital Carlos Haya	Malaga
Spain	Hospital Virgen de la Victoria	Malaga
Spain	Hospital de Navarra	Pamplona
Switzerland	Centre Hospitalier Universitaire	Lausanne
United States	Billings Clinic Montana	Billings	Montana
United States	Carolinas Medical Center- Carolinas Health Care System	Charlotte	North Carolina
United States	Compassionate Cancer Care Medical Group	Corona	California
United States	Centura Health Research Center	Denver	Colorado
United States	Barbara Ann Karmonos Cancer Hospital	Detroit	Michigan
United States	City of Hope	Duarte	California
United States	University of Connectcut Health Center	Farmington	Connecticut
United States	California Cancer Associates for Researche and Excellence	Fresno	California
United States	Penn State Hershey Cancer Institut	Hershey	Pennsylvania
United States	AMPM Research Clinic	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Winthrop University Hospital	Mineola	New York
United States	Vanderbilt Ingram Cancer Center	Nashville	Tennessee
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Compassionate Cancer Care Medical Group	Riverside	California
United States	Washington University School of medecine	Saint Louis	Missouri
United States	Central Coast Medical Oncology Corp.	Santa Maria	California
United States	21st Century Oncology of Arizona	Sun City	Arizona
United States	Montefiore Medical Center	The Bronx	New York

Sponsors (1)

Lead Sponsor	Collaborator
Onxeo

Countries where clinical trial is conducted

United States,  France,  Germany,  Hungary,  Spain,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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
Other	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
Other	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
Other	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
Other	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
Primary	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	At Least One Opioid Use (Class 3 Analgesic)	Opioid use was recorded twice weekly during the active phase (radiotherapy)	8 weeks
Secondary	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
Secondary	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
Secondary	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