| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with severe forms of Recurrent Aphthous Stomatitis (RAS) |
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| E.1.1.1 | Medical condition in easily understood language |
| Patients with severe forms of Recurrent Aphthous Stomatitis (RAS) |
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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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045372 |
| E.1.2 | Term | Ulcers aphthous oral |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
The primary objective of this study is to assess the superiority of apremilast in comparison with placebo to achieve sustained Complete Remission (CR) of oral ulcers, in patients with severe RAS resistant or intolerant to colchicine at Week 12 and Week 14 and Week 16.
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| E.2.2 | Secondary objectives of the trial |
1- To compare the efficacy of apremilast and placebo during the study on Double-blind phase and Active treatment phase:
• number of oral ulcers
• CR or almost CR
• Evolution of the objective oral Ulcer Severity Score (USS) (17)
• Patients Reported Outcome Measures (PROMS):
o Change in quality of life assessed by the SF36 and the Chronic Oral Mucosal Disease quality of life questionnaire.
o Cumulative duration of CR during the study
o Change in patients’ pain
o Change in psychosocial anxiety and depression scale
2- To compare the tolerance of apremilast and placebo (side effects).
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged ≥18 years old with severe primary RAS resistant to colchicine prescribed at a dose of 1mg/day or more for at least 3 months, or intolerant to colchicine
Severity of primary oral aphtous ulcer is defined by the presence at least one oral ulcer at the date of inclusion AND the presence of at least one of the following criteria:
i) At least one large / giant oral ulcer (≥ 1cm in diameter) confirmed by the investigator during the month preceding inclusion and/or,
ii) Multiple simultaneous oral ulcers (≥4), including herpetiform ulcers confirmed by the investigator during the month preceding inclusion and/or,
iii) Continuous evolution of oral ulcers, some lesions healing, as newly appearing oral ulcers develop within the month before inclusion and/or,
iv) Ulcers occurring at least 7 days each month during the previous 3 months (15) and/or
v) Major pain related to oral ulcers interfering with eating, speaking, or swallowing
2. Patient having read and understood the information letter and signed the Informed Consent Form
3. For women:
a. Women of childbearing potential :
i. Effective contraception according to CTFG contraception recommendations (V1.1 21/09/2020) since at least 4 weeks before randomization and during treatment,
and;
ii. Negative blood pregnancy test;
b. Women surgically sterile (absence of ovaries and/or uterus);
c. Postmenopausal women (non-medically induced amenorrhea for at least 12 months prior to the inclusion visit).
Abstinence is acceptable only if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception. Barrier methods must always be supplemented with the use of a spermicide.
4. Patient able to comply with the study protocol, in the investigator’s judgment
5. Patient affiliated with, or beneficiary of a social security (health insurance) category.
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|
| E.4 | Principal exclusion criteria |
1. History of clinically significant or uncontrolled disease (as determined by the investigator), which places the subject at unacceptable risk if he/she were to participate in the study.
2. Patient has secondary RAS (e.g., celiac disease, Crohn’s disease, ulcerative colitis, relapsing polychondritis, PFAPFA, AIDS…).
3. Depression and suicidal ideation, in particular prior history of suicide attempt at any time in the subject’s lifetime prior to signing the informed consent, or major psychiatric illness requiring hospitalization within the last 3 years prior to signing the informed consent.
4. Co-medication with a cytochrome P450 3A4 (CYP3A4) enzyme inducer (especially, rifampicin and most anti-epileptic drugs (e.g. carbamazepine, phenytoin)
5. Patient severely underweight patient (BMI < 16 kg/m2)
6. Patient cannot be followed regularly.
7. Patient has any other inflammatory oral disease, which confounds the ability to interpret data from the study (ie, lichen planus, auto immune bullous diseases with oral involvement),
8. Patient has any medical condition that requires systemic treatment which may confound the ability to interpret data from the study (ie, lupus erythematosus, rheumatoid arthritis...)
9. Hypersensitivity of the active substance(s) or to any of the excipients of OTEZLA and placebo
10. Patient is currently enrolled in any other therapeutic trial
11. Other than RAS, subject has any clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal, hematologic, immunologic disease, or other major disease that is currently uncontrolled in the opinion of the investigator.
12. Malignancy or history of malignancy or myeloproliferative or lymphoproliferative disease within the past 5 years, except for treated (ie, cured) basal cell or squamous cell carcinomas, in situ cervix carcinoma, or any situation in which the oncologist in charge of the patient considers that oncologic risk allows the use of apremilast.
13. Patients with positive blood test for HIV.
14. Any bacterial infections requiring treatment with oral or injectable antibiotics, or significant viral or fungal infections, within 4 weeks of Screening. Any treatment for such infections must have been completed and the infection cured, at least 4 weeks prior to Screening and no new or recurrent infections prior to the Baseline Visit.
15. Patient is a pregnant or breastfeeding (lactating) woman or intending to become pregnant during the study; Women who are not postmenopausal (≥ 12 months of non−therapy-induced amenorrhea) or surgically sterile must have a negative result from a serum pregnancy test within 1 week prior to randomization and use an effective contraception.
16. Patient has used systemic therapy which may potentially be effective in RAS within four weeks prior to randomization (including, but not limited to corticosteroids, azathioprine, levamisole, thalidomide)
17. Patient has used biologic therapy, including anti-TNF, within 5 pharmacokinetic half-lives of the administrated product.
18. Prior treatment with apremilast, or participation in a clinical study, involving apremilast.
19. Galactose intolerance, lactase deficiency or glucose/galactose malabsorption
20. Patient is deemed unreliable or for any reason not able to comply with the protocol
21. Patient with alcohol dependency
22. Person deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint will be sustained complete response (CR) (i.e., no oral ulcer at both the Week 12 and Week 14 and Week 16 evaluations), assessed by a blind evaluator (so that the evaluator will not be aware of any digestive complaints from the patient, that may be frequent with apremilast) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| both at Week 12, Week 14 and Week 16 |
|
| E.5.2 | Secondary end point(s) |
Double-blind phase
• Mean cumulative number of oral ulcers at the Week 12 and Week 14 and Week 16 evaluations.
• Proportion of patients with sustained “almost CR” (at most one new or persistent limited (< 2 mm) oral ulcer at the Week 12 and/or the Week 14 and/or the Week 16 evaluations).
• Delay of achievement of CR defined as the time at which patients have no new OU, and previous OU which have healed for at least 4 weeks
• Evolution of the Objective Ulcer Severity Score (USS) (17) from Baseline, Week 4, Week 8, Week 12, Week 14 and Week 16
NB: this score was previously shown to be highly reproducible among observers (17). However, to ensure a homogeneous rating between investigators, a training session on the use of this score will be organized for the investigators before the start of the study.
• Occurrence and type of severe and non-severe adverse events, the relationship of such events to apremilast,
NB: Special attention will be paid to adverse effects already described with apremilast such as gastro intestinal side effects, psychological distress and evolution of weight.
• Premature discontinuation of the study medication or dose reduction owing to any adverse event
• Patients’ reported outcomes:
As underlined in the systematic review, four Patients’ Reported Outcome Measures (PROMs) will be used in this study:
i) Quality of life will be evaluated at baseline, Week 4, Week 8, Week 12, Week 14, and Week 16 with the use of the SF36 questionnaire (68), and the Chronic Oral Mucosal Disease quality of life questionnaire (69).
NB: Despite the fact that the French version of the COMD questionnaire is not validated, we will use this questionnaire and validate its French version since the only validated French version of an oral QOL questionnaire : the GOHAI questionnaire (70) is focused on theeth and not adapted to diseases of the oral mucosa
ii) Cumulative duration of periods of CR ( no pain, no oral ulcer) during the double blind phase from baseline to Week 16 evaluated by a follow-up diary in which patients will note every day whether or not they have oral ulcers and if so, how many.
NB: Based on the investigators' experience and for feasibility reasons, only the cumulative duration of the CR periods will be compared between the two treatment groups (and not the cumulative duration of almost CR periods), since while the absence of oral ulcer and pain seems easy for patients to assess reliably, adding periods with a single oral ulcer may likely lead to great variability between patients.
iii) Change in pain from oral ulcers from baseline to Week 16 (Baseline, Week 4, Week 8, Week 12, Week 14, Week 16), as measured on a 100 mm visual-analogue scale (with 0 representing no pain and 100 the worst pain ever experienced),
iv) Psychosocial-PROMs, which will be assessed at baseline, Week 4, Week 8, Week 12, Week 14, and Week 16, using the Hospital Anxiety and Depression (HADS) scale (71).
• Occurrence and type of severe and non-severe adverse events, the relationship of such events to apremilast,
NB: Special attention will be paid to adverse effects already described with apremilast such as gastro intestinal side effects, psychological distress and evolution of weight.
• Number of patients with SAEs leading to drug premature discontinuation or dose reduction
Active treatment phase:
• Proportion of patients with sustained “almost CR” (at most one new or persistent limited (< 2 mm) oral ulcer at Week 28)
• Proportion of patients in CR at Week 28
• Number of new oral ulcers at Week 28,
• Objective Ulcer Severity Score (USS) at Week 16, Week 20 and Week 28
• Patients’ reported outcomes:
• i) Quality of life will be evaluated at Week 16, Week 20 and Week 28 with the use of the SF36 questionnaire (68), and the and the Chronic Oral Mucosal Disease quality of life questionnaire (69) .
• ii) Change in pain from oral ulcers from Week 16 to Week 28 (Week 16, Week 20 and Week 28), as measured on a 100 mm visual-analogue scale (with 0 representing no pain and 100 the worst pain ever experienced),
• iii) Psychosocial-PROMs, which will be assessed at Week 16, Week 20 and Week 28, using the Hospital Anxiety and Depression (HADS) scale (71).
• Occurrence and type of severe and non-severe adverse events, the relationship of such events to apremilast,
NB: Special attention will be paid to adverse effects already described with apremilast such as gastro intestinal side effects, psychological distress and evolution of weight.
• Number of patients with SAEs leading to drug premature discontinuation or dose reduction |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Week 4, Week 8, Week 12, Week 14, Week 16, Week 20 and Week 28 |
|
| 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 | Yes |
| E.6.4 | Safety | No |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| 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 | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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 | 2 |
| 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 | 17 |
| E.8.5 | The trial involves multiple Member States | No |
| 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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| the end of the trial is the last visit of the last subject undergoing the trial |
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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 | 7 |
| E.8.9.1 | In the Member State concerned days | |
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