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 |
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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 |
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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 |
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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 |
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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 |
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E.2.3 | Trial contains a sub-study | No |
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
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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
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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
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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 |
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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) |
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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) |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | Yes |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 3 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | No |
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
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From the first inclusion to the last visit of the last subject. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |