Efficacy and Safety of Apremilast Versus Placebo in Severe Recurrent Aphthous Stomatitis Resistant or Intolerant to Colchicine: A Randomized Controlled Trial
- Trial ID
- 2024-514659-13-00
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **superiority** of apremilast compared to placebo in achieving sustained Complete Remission (CR) of oral ulcers in patients with severe Recurrent Aphthous Stomatitis (RAS) who are resistant or intolerant to colchicine. This assessment will be conducted at Weeks 12, 14, and 16. The clinical relevance of this objective lies in addressing the therapeutic needs of patients with severe RAS, a condition characterized by painful oral ulcers, which significantly impacts quality of life. By determining the efficacy of apremilast, the study aims to provide an alternative treatment option for those who do not respond to or cannot tolerate existing therapies.
Participants
The clinical trial involves **patients with severe forms of Recurrent Aphthous Stomatitis (RAS)** who are resistant or intolerant to colchicine. The study population includes both male and female participants aged 18 years and older. Participants are required to have severe primary RAS, characterized by at least one large oral ulcer or multiple simultaneous oral ulcers, among other criteria, confirmed by an investigator within the three months preceding inclusion. The trial does not involve a vulnerable population. Participants must have read and understood the information letter and signed the informed consent form. Women of childbearing potential are required to use effective contraception and have a negative blood pregnancy test. The sponsor has not provided the total number of participants in the trial. Participants are expected to comply with the study protocol and be affiliated with a social security or health insurance category. The trial population was selected based on specific inclusion criteria, ensuring that participants have a consistent history of severe RAS symptoms and are able to adhere to the study requirements.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, **controlled** study to evaluate the safety and efficacy of **apremilast** compared to a placebo in patients with severe forms of **recurrent aphthous stomatitis** (RAS). The primary objective is to determine the superiority of apremilast in achieving sustained complete remission of oral ulcers in patients resistant or intolerant to colchicine at Weeks 12, 14, and 16. The trial is expected to run from April 2022 to April 2026, with participant involvement lasting up to 16 weeks.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, severity of RAS, and previous treatment history. Eligible participants will be randomly assigned to receive either apremilast or a placebo. The study drug will be administered orally, with a maximum daily dose of 60 mg. Follow-up visits will occur at regular intervals to monitor the participants' response to treatment and assess any adverse effects. The primary endpoint, sustained complete response, will be evaluated by a blind evaluator at Weeks 12, 14, and 16.
The end-of-study visit will mark the conclusion of the participant's involvement, during which final assessments will be conducted to evaluate the overall treatment efficacy and safety. Participants may be withdrawn from the study early if they experience significant adverse effects, fail to comply with the study protocol, or choose to withdraw consent. The trial is conducted in accordance with ethical guidelines, ensuring that all participants provide informed consent prior to enrollment.
Treatment
The clinical trial involves the administration of **apremilast**, an experimental medication, to evaluate its efficacy and safety in patients with severe recurrent aphthous stomatitis. **Apremilast** is provided in the form of a **film-coated tablet** and is administered orally. The maximum daily dose is 60 mg, with a total maximum dose of 11460 mg over a treatment period of 7 days. The active substance, **apremilast**, is of chemical origin. Participants are required to adhere to the dosing schedule, and compliance will be monitored throughout the study.
The study also includes a **placebo** group to serve as a comparator for the experimental treatment. The placebo is designed to mimic the appearance of the **apremilast** tablets but does not contain any active pharmaceutical ingredients. The placebo is administered in the same manner as the experimental medication, ensuring that the study remains double-blind. Participants receiving the placebo will follow the same dosing schedule as those receiving **apremilast**. Compliance with the placebo regimen will also be monitored to ensure the integrity of the trial results.
Efficacy
The efficacy of the investigational product, **apremilast**, will be assessed in a randomized, double-blind, controlled trial comparing its effects to a placebo in patients with severe recurrent aphthous stomatitis (RAS) resistant or intolerant to colchicine. The primary objective is to evaluate the superiority of apremilast in achieving sustained Complete Remission (CR) of oral ulcers. The primary endpoint for efficacy is defined as the absence of oral ulcers at the evaluations conducted at Week 12, Week 14, and Week 16. This assessment will be performed by a blind evaluator to ensure objectivity, with the evaluator being unaware of any digestive complaints from the patient, which may be frequent with apremilast.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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.i) At least one large / giant oral ulcer (≥ 1cm in diameter) confirmed by the investigator during the 3 months month preceding inclusion and/or, ii) Multiple simultaneous oral ulcers (≥4), including herpetiform ulcers confirmed by the investigator during the 3 months preceding inclusion and/or, iii) Continuous evolution of oral ulcers, some lesions healing, as newly appearing oral ulcers develop within the 3 months 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
- Patient having read and understood the information letter and signed the Informed Consent Form
- 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.
- Patient able to comply with the study protocol, in the investigator’s judgment
- Patient affiliated with, or beneficiary of a social security (health insurance) category
Exclusion Criteria
- 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.
- Patient has secondary RAS (e.g., celiac disease, Crohn’s disease, ulcerative colitis, relapsing polychondritis, PFAPFA, AIDS…).
- 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.
- Co-medication with a cytochrome P450 3A4 (CYP3A4) enzyme inducer (especially, rifampicin and most anti-epileptic drugs (e.g. carbamazepine, phenytoin)
- Patient severely underweight patient (BMI < 16 kg/m2)
- Patient cannot be followed regularly
- 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),
- 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...)
- Hypersensitivity of the active substance(s) or to any of the excipients of OTEZLA and placebo
- Hypersensitivity of the active substance(s) or to any of the excipients of racecadotril
- Patient is currently enrolled in any other therapeutic trial
- Other than RAS, subject has any clinically significant (as determined by the Investigator) cardiac, endocrinologic, pulmonary, neurologic, psychiatric, hepatic, renal (defined by creatinine clearance <30 mL / min estimated by Cockroft-Gault equation), hematologic, immunologic disease, or other major disease that is currently uncontrolled in the opinion of the investigator
- 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.
- Patients with positive blood test for HIV.
- Any severe 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.
- Patient 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.
- 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)
- Patient has used biologic therapy, including anti-TNF, within 5 pharmacokinetic half-lives of the administrated product.
- Prior treatment with apremilast, or participation in a clinical study, involving apremilast.
- Galactose intolerance, lactase deficiency or glucose/galactose malabsorption
- Patient is deemed unreliable or for any reason not able to comply with the protocol
- Patient with alcohol dependency
- Persons referred to in articles L1121-5 to L1121-8 of the CSP (pregnant or breastfeeding (lactating) woman, deprived of liberty by administrative or judicial decision or placed under judicial protection (guardianship or supervision)
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Yet Recruiting | 10 Apr 2022 | 134 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
Placebo of apremilast | Placebo | N/A | — | — | — | N/A |
APREMILAST | Test | — | ORAL USE | 60 | 7 | SUB130837 |
RACECADOTRIL | Other | — | ORAL | 200 | 7 | SUB12435MIG |