Clinical Trials Register

Summary
EudraCT Number:	2009-014870-16
Sponsor's Protocol Code Number:	BA2009-28-01
National Competent Authority:	Germany - BfArM
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2011-01-26
Trial results	View results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Germany - BfArM

A.2

EudraCT number

2009-014870-16

A.3

Full title of the trial

A phase II, multicentre, 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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Clinical study to evaluate the safety and efficacy of a mucoadhesive buccal tablet to treat mucositis (inflammation of the oral mucosa) due toradiotherapy and chemotherapy in patients treated for a head and neck cancer

A.4.1

Sponsor's protocol code number

BA2009-28-01

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Onxeo
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Onxeo
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Onxeo
B.5.2	Functional name of contact point	Clinical research department
B.5.3	Address:
B.5.3.1	Street Address	49, boulevard du Général Martial Valin
B.5.3.2	Town/ city	Paris
B.5.3.3	Post code	75015
B.5.3.4	Country	France
B.5.4	Telephone number	+33 (0) 1 45 58 76 00
B.5.5	Fax number	+33 (0) 1 45 58 08 81
B.5.6	E-mail	b.vasseur@onxeo.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/919
D.3 Description of the IMP
D.3.1	Product name	Clonidine Lauriad™
D.3.2	Product code	BA028
D.3.4	Pharmaceutical form	Muco-adhesive buccal tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Gingival use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLONIDINE
D.3.9.1	CAS number	4205907
D.3.9.2	Current sponsor code	BA028
D.3.9.3	Other descriptive name	Clonidine Lauriad™
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No
D.IMP: 2
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/11/919
D.3 Description of the IMP
D.3.1	Product name	Clonidine Lauriad™
D.3.2	Product code	BA028
D.3.4	Pharmaceutical form	Muco-adhesive buccal tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Gingival use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	CLONIDINE
D.3.9.1	CAS number	4205907
D.3.9.2	Current sponsor code	BA028
D.3.9.3	Other descriptive name	Clonidine Lauriad™
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	100
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Muco-adhesive buccal tablet
D.8.4	Route of administration of the placebo	Gingival use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Prevention and treatment of oral mucositis in head and neck cancer patients undergoing chemo-radiation therapy

E.1.1.1

Medical condition in easily understood language

Prevention and treatment of an oral inflammation and pain due to chemo-radiotherapy for head and neck cancer

E.1.1.2

Therapeutic area

Diseases [C] - Mouth and tooth diseases [C07]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	17.0
E.1.2	Level	PT
E.1.2	Classification code	10037763
E.1.2	Term	Radiation mucositis
E.1.2	System Organ Class	10022117 - Injury, poisoning and procedural complications

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate the efficacy of clonidine Lauriad™ 50 μg and 100 μg MBT versus placebo in the prevention and treatment of chemoradiation therapy induced oral mucositis

E.2.2

Secondary objectives of the trial

- To determine the optimal dose of clonidine Lauriad™ MBT
- To determine the plasma and salivary pharmacokinetic parameters of clonidine Lauriad™ 50 μg and 100 μg MBT
- To evaluate the quality of life of cancer patients treated with clonidine Lauriad™ MBT during chemoradiation therapy
- To evaluate the duration of MBT adhesion.
- To evaluate the local and overall safety of clonidine Lauriad™ MBT
- To preliminary evaluate the health economics in patients undergoing chemoradiotherapy treated with clonidine Lauriad™ MBT and placebo
- To evaluate overall survival and disease progression in each group

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female
2. Aged >18 years
3. Suffering from a newly diagnosed squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx or larynx histologically-confirmed and having undergone resective surgery
4. Prior neoadjuvant chemotherapy allowed provided that, the patient did not experience a WHO
grade > 2 oral mucositis during the neoadjuvant therapy.
5. Patient eligible to receive concurrent chemo-radiation defined as :
a. A continuous course of conventional external beam irradiation (IMRT eligible) with a minimum cumulative radiation dose of 50 Gy and 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
b. Planned radiation treatment fields must include at least two oral tissue sites (among right or left buccal mucosa, floor of the 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.
6. ECOG performance status ≤ 2
7. Screening laboratory tests
a. Haemoglobin ≥ 10g/dL (100 g/L)
b. Absolute neutrophil counts ≥ 1500 cells/mm3 (1.5 109 cells/L)
c. Platelets ≥ 100.000/mm3 (100 109/L)
d. Conjugated bilirubin ≤ 2 times Upper Limit of Normal (ULN)
e. Serum AST and ALT ≤ 3 ULN
f. Negative serum pregnancy test
8. Women of child bearing potential must have effective contraception method (oral or device)
9. Signed written informed consent

E.4

Principal exclusion criteria

1. Tumours of the lips, sinuses, salivary glands
2. Prior radiation of the head and neck area
3. Curative surgery less than 2 weeks or more than 15 weeks prior to the initiation of RT-CT
4. Presence of active infectious disease
5. Presence of active oral infectious disease, including oropharyngeal candidiasis and/or orofacial herpes
6. Presence of oral mucositis
7. Known or suspected chronic viral diseases including HIV
8. Systolic blood pressure <100 mmHg and/or diastolic blood pressure <50 mmHg
9. Recent stroke within the last 6 months
10. Bradyarrhythmia (< 60 b/min), including sinus node dysfunction or AV nodal conduction block 2nd or 3rd degree.
11. Subjects with orthostatic hypotension, defined by a decrease of systolic BP and/or diastolic BP above 20 mmHg when the patient stands up
12. Renal insufficiency defined as creatinine blood level > 1.5ULN
13. Ongoing heavy alcohol consumption (>100g alcohol/day)
14. Administration of any concomitant treatment likely to interfere with clonidine (see section 6.4)
15. Known hypersensitivity to clonidine, history of allergy or intolerance to milk proteins or any other component of the product
16. Presence of severe or uncontrolled depression
17. Pregnant or breast-feeding women
18. Inability to give informed consent or comply with study requirements
19. Unable or unwilling to comply with follow-up visits
20. Participation to a clinical trial within 30 days prior to randomization and during the entire duration of the study

E.5 End points

E.5.1

Primary end point(s)

Comparison between groups of the percentage of patients with an oral mucositis score ≥ 3 using the WHO scale at cumulative radiation dose of 50 Gy

E.5.1.1

Timepoint(s) of evaluation of this end point

Evaluation of the WHO score by the investigator: at randomisation before treatment, twice a week during the 8 weeks of treatment, one month after the end of the treatment

E.5.2

Secondary end point(s)

comparison between groups of
- Percentage of patients with an oral mucositis score ≥ 3 using the WHO scale at cumulative radiation doses of 40 Gy and 60 Gy
- Time to onset of severe oral mucositis ( WHO Score ≥ 3)
- Area under the curve of oral mucositis scores
- Duration of grade 3/4 mucositis
- Overall incidence of grade 3/4 mucositis at any time
- Percentage of patients with OMDQ Question 2 scores >2 at cumulative radiation doses of 40 Gy, 50 Gy, and 60 Gy
- Incidence, duration and total dose (in morphine equivalent) of opioids use
- Number of days during which the use of gastrostomy or nasogastric tube for feeding is necessary and total number of calories administered
- Unplanned office or emergency room visits
- Number of days of hospitalisation
- Weight loss
- Compliance to clonidine Lauriad™ (50 μg and 100 μg) MBT and placebo
- Adhesion duration of MBT, incidence of detachment and/or swallow and number of tablets replaced
- PK plasma parameters including Cmax, AUC o-t, AUC o-∞, Tmax, t1/2, tlag, ke
- PK salivary parameters including Cmax, AUC o-t and Tmax
- Relationship between concentrations of clonidine in saliva and efficacy and tolerance criteria
- Overall tolerability: incidence, severity and nature of adverse events and SAE
- Local tolerability
- Haematological and biochemical tolerance
- Overall survival (OS) and Time to Progression (TTP)

E.5.2.1

Timepoint(s) of evaluation of this end point

Evaluation of the WHO score by the investigator: before treatment, twicea week during the 8 weeks of treatment, one month after the end of the treatment.
Evaluation of the safety at each visit : the screening visit (V1), twice a week during the treatment (V2-V18) and at the end of study visit (V19)

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

Yes

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

From the first inclusion to the last visit of the last subject.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

160

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

163

F.4.2.2

In the whole clinical trial

183

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Not applicable

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2011-04-08

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-05-03

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2014-08-20

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