Patients with severe forms of Recurrent Aphthous Stomatitis (RAS) MedDRA version: 20.0 Level: LLT Classification code 10045372 Term: Ulcers aphthous oral System Organ Class: 100000004856
Conditions
Interventions
Trade Name: Otezla
Pharmaceutical Form: Tablet
INN or Proposed INN: Apremilast
CAS Number: 608141-41-9
Concentration unit: millilitre(s)/gram
Concentration type: range
Concentration number: 10-30
Phar
Sponsors
CHU de Rouen
Eligibility
Sex/Gender
All
Inclusion criteria
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. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 100 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 34
Exclusion criteria
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 protecti
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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. ;Secondary Objective: 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): oChange in quality of life assessed by the SF36 and the Chronic Oral Mucosal Disease quality of life questionnaire. oCumulative duration of CR during the study oChange in patients’ pain oChange in psychosocial anxiety and depression scale 2- To compare the tolerance of apremilast and placebo (side effects). ;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);Timepoint(s) of evaluation of this end point: both at Week 12, Week 14 and Week 16 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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 d | — |
Countries
France
Contacts
Public ContactMALLET
CHU de Rouen
Outcome results
None listed