Efficacy and Safety of Roflumilast Cream 0.3% in Subjects With Plaque Psoriasis: a Phase 3 Study

A Multicenter, Randomized, Double-blind, Vehicle-controlled Phase 3 Clinical Study To Evaluate The Efficacy and Safety Of Roflumilast Cream 0.3% (Zoryve®) in the Treatment of Plaque Psoriasis In China

This study is a multi-center, randomized, double-blind, vehicle-controlled phase III study to evaluate the efficacy, safety, and PK profile of roflumilast cream 0.3% in Chinese subjects ≥6 years of age with plaque psoriasis.

Inclusion Criteria:

1. Fully understand the objectives and requirements of this study, voluntarily participate in the clinical trial and sign the informed consent form (ICF), and be able to complete all visits as required by the protocol.

2. Aged ≥ 6 years at the time of signing the ICF, male or female.

3. Clinical diagnosis of plaque psoriasis before the first dose in this study, with a disease duration of ≥ 6 months (for those aged ≥ 12 years) or ≥ 3 months (for those aged 6-11 years) and stable for the last 4 weeks.

4. Patients are required to meet the following requirements at screening and baseline:

   • Psoriasis involving 2%-20% BSA (excluding the scalp, palms, and soles);
   • IGA score of ≥ 2 points;
   • PASI score of ≥ 2 points (excluding the scalp, palms, and soles).

5. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at Screening and a negative urine pregnancy test at Baseline. FOCBP must agree to take at least one reliable form of birth control, including oral/implantable/injectable/transdermal contraceptive, intrauterine device, bilateral tubal ligation/occlusion, partner's vasectomy, and barrier contraception (used correctly throughout sexual intercourse), from 4 weeks before the first dose of the IMP until 2 months after the last dose. If the subject is routinely abstinent, the subject may use this form of contraception, but should choose a reliable form of contraception as mentioned above if the subject is no longer abstinent. Male subjects will be required to have no plans to have children, no plans to donate sperm, and agree to use highly effective contraception. from the first dose of the investigational medicinal product until 4 months after the last dose.

   Note: FOCBP are defined as female subjects who have experienced menarche, have not reached a postmenopausal state (amenorrhea for at least 12 consecutive months, with no clear cause other than menopause and confirmd by FSH), and have no surgical (i.e., bilateral oophorectomy and/or bilateral salpingectomy and/or hysterectomy) or investigator-determined causes of permanent infertility (e.g., mullerian agenesis, etc.).

6. Subjects were assessed by the investigator to be free of other medical conditions that would interfere with the assessment of safety and efficacy based on medical history, physical examination, routine blood, blood biochemistry, urine, and other laboratory tests.

Exclusion Criteria:

1. Non-plaque psoriasis (e.g., guttate psoriasis, pustular psoriasis, erythrodermic psoriasis, and arthropathic psoriasis) or drug-induced psoriasis.

2. Skin disorders or other conditions that, in the judgment of the investigator, may interfere with the assessment of endpoints relevant to this study, including but not limited to: viral lesions, fungal and bacterial skin infections, parasitic infections, syphilis or tuberculosis-related skin manifestations, etc.

3. Prior use of etanercept within 4 weeks before the first dose of this study, or use of adalimumab and/or infliximab within 8 weeks before the first dose of this study, or prior use of another biologic within 12 weeks before the first dose of this study (or within 5 half-lives of the biologic at the time of the first dose of this study, whichever is longer).

4. Prior use of systemic drugs for psoriasis treatment or any other agents which may impact efficacy assessment of psoriasis, including but not limited to oral or intravenous glucocorticoids, retinoic acids, methotrexate, cyclosporine, and other systemic immunosuppressive agents or a class of drugs (including Chinese herbal formulas, herbs, proprietary Chinese medicines, etc.) containing Chinese medicinal ingredients within 4 weeks of the first dose of this study.

5. Prior use of topical agents for psoriasis treatment or any other agents which may impact efficacy assessment of psoriasis, including but not limited to topical glucocorticoids, vitamin D analogues, benvitimod and prescription emollients or emollients containing additives (e.g., ceramides, hyaluronic acid, urea, or filamentous proteolytic products) or antipruritic ingredients (e.g., menthol, polyhydroxyethanol, pramoxine, lidocaine, prilocaine, capsaicin, naltrexone, N-palmitoylethanolamine, etc.) or a class of drugs (including Chinese herbal formulas, herbs, proprietary Chinese medicines, etc.) containing Chinese medicinal ingredients for topical use (Note: for the treatment of diseases other than psoriasis, except in cases where the use of such medicines is deemed necessary in the medical judgment of the investigator and/or the specialist and would not interfere with the assessment of the study), etc. within 2 weeks.

6. Prior use of psoralen plus ultraviolet A (PUVA) or ultraviolet B (UVB) phototherapy within 4 weeks before the first dose of this study.

7. Prior use of ZORYVE® cream or foam; prior use of oral roflumilast or other phosphodiesterase-4 (PDE4) inhibitors (apremilast, etc.) within 4 weeks prior to the first dose of this study.

8. Prior use of antihistamines, potent cytochrome P (CYP) 450 enzyme inhibitors (such as indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole, ketoconazole, nefazodone, saquinavir and telithromycin) or inducers (such as efavirenz, barbiturates, phenytoin sodium, and rifampicin) within 2 weeks before the first dose of this study or these drugs cannot be discontinued during the study.

9. Prior use of lithium-containing agents or antimalarials within 4 weeks (or 5 half-lives, whichever is longer) prior to the first dose of this study..

10. Subjects who are expected to have excessive exposure to natural/artificial light, sunbeds, or other light-emitting diode (LED) irradiation at the treatment area during the treatment period of this study.

11. Planned initiation or change in the use of an existing medication (e.g., beta-blockers or angiotensin-converting enzyme inhibitors) that, in the opinion of the investigator, can affect the efficacy evaluation for psoriasis.

12. Known hypersensitivity to roflumilast or any of the excipients of the product (white vaseline, isopropyl palmitate, hydroxybenzyl ester, propyl hydroxybenzoate, diethyleneglycol monoethyl ether, hexanediol, hydrochloric acid dilute, sodium hydroxide, Crodafos CES [including cetearyl alcohol, cetyl phosphate, and ceteareth-10 phosphate]).

13. Previous or suspected human immunodeficiency virus (HIV) infection, or HIV antibody-positive at screening; or hepatitis B (hepatitis B virus surface antigen [HBsAg])-positive or HBsAg-negative but hepatitis B virus core antibody (HBcAb)-positive, in which case DNA quantitation should be detected and the result is higher than the upper limit of normal; or hepatitis C (hepatitis C virus [HCV]) antibody-positive with HCV-RNA quantification above the upper limit of normal value; or syphilis screening-positive (except for patients with a positive specific antibody test, a negative non-specific antibody test, and confirmed as inactive infection in combination with clinical judgment).

14. As judged by the investigator, with known or suspected:

    • Moderate to severe hepatic impairment (Child-Pugh B/C) at screening. See Appendix 16.7 for Child-Pugh grading criteria
    • Total bilirubin and or AST and or ALT > 1.5 x ULN at screening
    • SCr > 1.5 x ULN at screening
    • History of major depressive disorder, suicidality, or suicidal tendency suggested by the C-SSRS at baseline or screening.

15. PHQ-8 (adults) or modified PHQ-A (aged 12-17 years) ≥ 10 points, for children aged 6-11 years, investigators assessed the presence or risk of depression after communicating with their parents/guardians at baseline or screening.

16. Female subjects in the lactating period; or subjects who have a fertility plan during the study.

17. Alcohol (defined as >2 units of alcohol per day/>14 units of alcohol per week, with 1 unit of alcohol equivalent to 360 mL of beer or 45 mL of spirits with 40% alcohol content or 150 mL of wine) or drug abuse within 6 months before screening in this study.

18. Have undergone a major surgery within 4 weeks prior to the first dose of this study (for the definition of major surgery, refer to Level 3 and Level 4 surgeries specified in the "Measures for the Classification of Surgical Procedures in Medical Institutions" issued by the National Health Commission of the People's Republic of China on Dec. 6, 2022) or plan to undergo a major surgery during the study.

19. Cancer (except for non-melanoma skin cancer, localized prostate cancer, ductal carcinoma in situ, stage I uterine cancer, cervical carcinoma in situ, or breast carcinoma in situ that have been treated with curative therapy) within 5 years before the first dose of this study.

20. Prior active infection requiring the use of oral or intravenous antibiotics, antifungal or antiviral agents within 7 days before the first dose of this study.

21. Any serious disease or medical measure, physical or mental condition that, in the opinion of the investigator, will affect the subject's participation in the trial (including the use of IMP and participation in required study visits), or that, in the opinion of the investigator, will pose a significant risk or effect to the subject.

22. Family members involving staff from the clinical research organization, contract research organization (CRO, if applicable), or sponsor participated in the design or conduct of this study, or a family member has already been enrolled in this study.

23. Currently participating in any other interventional clinical trials; or participation in a pharmaceutical clinical trial within 3 months or 5 half-lives (whichever is longer) or any other interventional clinical trial within 3 months prior to the first dose of this study.

24. Other reasons judged by the investigator as inappropriate for enrollment in this study.