Randomized Double Blind Controlled Trial Comparing the Safety and Efficacy of Apremilast Versus Placebo in Severe Forms of Recurrent Aphthous Stomatitis

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 of at least one of the following criteria: i) - At least one 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) - Oral ulcers occurring at least 7 days each month during the previous 3 months and/or v) - Major pain related to oral ulcers interfering with eating, speaking, or swallowing \- In all cases, patients must have at least one oral ulcer on the date of inclusion 2\. Patient having read and understood the information letter and signed the Informed Consent Form 3. For women who are not postmenopausal and who do not plan on having children anymore: agreement to remain abstinent or use two adequate methods of contraception 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 Exclusion Criteria: 1. Patient has any significant medical condition, significant laboratory abnormality, or psychiatric illness that would prevent the subject from participating 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 4. Co-medication with a cytochrome P450 3A4 (CYP3A4) enzyme inducer ( especially, rifampicin and most anti-epileptic drugs (e.g. carbamazepine, phenytoin) 5. Severely underweight patient (BMI \< 18.5 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. Patient is currently enrolled in any other therapeutic trial. 10. 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. 11. 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. 12. Patient with positive blood test for HIV. 13. 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. 14. Patient has received a live vaccine within 3 months of baseline or plans to do so during study. 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. 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. 18. Prior treatment with apremilast, or participation in a clinical study, involving apremilast. 19. Patient has any condition including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study. 20. Galactose intolerance, lactase deficiency or glucose/galactose malabsorption 21. Patient is deemed unreliable or for any reason not able to comply with the protocol 22. Patient with alcohol dependency 23. Male patient intending to conceive a child with his partner