Randomized double blind controlled trial comparing the safety and efficacy of apremilast versus placebo in severe forms of recurrent aphthous stomatitis - PREMS - 2019/0411/HP

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Centre Hospitalier Universitaire Rouen

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Stomatognathic Diseases [C07], Diseases [C] - Skin and Connective Tissue Diseases [C17]

Decision date (initial)

2024-09-16

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514659-13-00

EudraCT number

2021-001964-11

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Therapy, Efficacy

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.

Conditions and MedDRA coding

Patients with severe forms of Recurrent Aphthous Stomatitis (RAS)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. 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.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
2. 2. Patient having read and understood the information letter and signed the Informed Consent Form
3. 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. 4. Patient able to comply with the study protocol, in the investigator’s judgment
5. 5. Patient affiliated with, or beneficiary of a social security (health insurance) category

Exclusion criteria 23

1. 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. 2. Patient has secondary RAS (e.g., celiac disease, Crohn’s disease, ulcerative colitis, relapsing polychondritis, PFAPFA, AIDS…).
3. 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. 4. Co-medication with a cytochrome P450 3A4 (CYP3A4) enzyme inducer (especially, rifampicin and most anti-epileptic drugs (e.g. carbamazepine, phenytoin)
5. 5. Patient severely underweight patient (BMI < 16 kg/m2)
6. 6. Patient cannot be followed regularly
7. 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. 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. 9. Hypersensitivity of the active substance(s) or to any of the excipients of OTEZLA and placebo
10. 10. Hypersensitivity of the active substance(s) or to any of the excipients of racecadotril
11. 11. Patient is currently enrolled in any other therapeutic trial
12. 12. 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
13. 13. 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.
14. 14. Patients with positive blood test for HIV.
15. 15. 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.
16. 16. 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.
17. 17. 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)
18. 18. Patient has used biologic therapy, including anti-TNF, within 5 pharmacokinetic half-lives of the administrated product.
19. 19. Prior treatment with apremilast, or participation in a clinical study, involving apremilast.
20. 20. Galactose intolerance, lactase deficiency or glucose/galactose malabsorption
21. 21. Patient is deemed unreliable or for any reason not able to comply with the protocol
22. 22. Patient with alcohol dependency
23. 23. 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)

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Centre Hospitalier Universitaire Rouen

Sponsor organisation

Centre Hospitalier Universitaire Rouen

Address

1 Rue De Germont, Bp 96031 Bp 96031

City

Rouen Cedex

Postcode

76031

Country

France

Scientific contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

Nell MARTY

Public contact point

Organisation

Centre Hospitalier Universitaire Rouen

Contact name

Nell MARTY

Locations

1 EU/EEA country · 21 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 10 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications