Efficacy and Safety of add-on Apremilast Versus add-on Methotrexate in Patients With Oral Lichen Planus

Efficacy and Safety of add-on Apremilast Versus add-on Methotrexate in Patients With Oral Lichen Planus: A Randomized Controlled Trial

Lichen planus is an inflammatory disorder of unknown aetiology affecting the stratified squamous epithelia, with an estimated global prevalence of 0.22 to 0.5 %. Oral mucosa (Oral Lichen Planus; OLP) is the most commonly affected region. Corticosteroids are the primary treatment of choice. A prolonged treatment with steroids is required for clinical improvement, which increases the chances of long-term adverse effects. So, there is a need for newer, effective treatment modalities, such as retinoids, methotrexate, Janus kinase inhibitors, PDE4 inhibitors, etc.

Of these, methotrexate is a dihydrofolate reductase inhibitor that inhibits the replication and function of T and B lymphocytes. It has shown a good response to OLP (around 83%) in a study by Lajevardi et al. and can be considered a treatment option in patients with moderate to severe OLP. Apremilast is a drug with a novel immunomodulatory mechanism of action. It inhibits phosphodiesterase type IV, which increases levels of cyclic adenosine monophosphate (cAMP), thus activating protein kinase A and inhibiting various inflammatory mediators. Based on a pilot study by Paul et al., apremilast is associated with clinical improvement in lichen planus.

Among the various treatment options, there is a lack of head-on trials. Methotrexate is an immunosuppressant with various systemic adverse effects and requires close monitoring. Whereas apremilast is a non-immunosuppressive drug with a better safety profile, it does not show such adverse effects. These drugs can be used as an add-on to low-dose steroids in view of reducing the adverse effects associated with steroid therapy. To the best of our knowledge, there is no randomized controlled trial comparing these two drugs to date. Hence, the present study has been planned to evaluate the safety and efficacy of methotrexate versus apremilast as an add-on to the standard steroid therapy in OLP patients.

Study Overview

• Status: Not yet recruiting
• Conditions: Oral Lichen Planus
• Intervention / Treatment: Drug: Prednisolone; Drug: Methotrexate; Drug: Apremilast

• Study Type: Interventional
• Enrollment (Estimated): 64
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Monalisa Jena, MD; Phone Number: 09438884193; Email: pharm_monalisa@aiimsbhubaneswar.edu.in
• Study Contact Backup: Name: Biswanath Behera, MD; Phone Number: 07978351200; Email: dermat_biswanath@aiimsbhubaneswar.edu.id

Study Locations

• India
  • Odisha
    • Bhubaneswar, Odisha, India, 751019
      • AIIMS Bhubaneswar
      • Sub-Investigator: Biswanath Behera
      • Contact: Monalisa Jena, MD; Phone Number: 09438884193; Email: pharm_monalisa@aiimsbhubaneswar.edu.in
      • Contact: Biswanath Behera, MD; Phone Number: 07978351200; Email: dermat_biswanath@aiimsbhubaneswar.edu.id
      • Principal Investigator: Madhusmita Sethy
      • Principal Investigator: Mowdharani PS

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients aged ≥18 of either sex with the clinical diagnosis of oral lichen planus.
• Patients with a PGA score of ≥3 (moderate and severe oral LP).
• Patient not responding to topical or intralesional corticosteroid.
• Patients who are willing to give informed written consent.

Exclusion Criteria:

• Treatment with a systemic corticosteroid within the last 4 weeks.
• Patients on any immunosuppressive agents such as azathioprine, cyclosporine and others within one month of recruitment.
• Patients with clinical history and any lesion distribution suspicious of a lichenoid drug eruption and patients with other skin diseases.
• Past or current history of any malignancy including moderate to severe dysplasia of the oral mucosa on oral biopsy.
• Severe active infection, including active tuberculosis, hepatitis B or C infection
• Patients with cytopenia (Hb <9g/dl, leukocyte count <4000/mm3, platelet count <100,000/mm3)
• Patient with history of alcohol abuse.
• Decreased liver or renal function (creatinine > 2.0mg/dl, total bilirubin > 2.5 mg/dl).
• Severe acute infection, uncontrolled diabetes mellitus, untreated glaucoma, congenital or acquired immunodeficiency, active gastroduodenal ulcer, severe osteoporosis, severe cardiac disease (NYHA grade IV), MI in the last four weeks, severe schizophrenia or depression.
• Patient with a history of hypersensitivity to Methotrexate or Apremilast.
• Pregnancy and lactation, women of childbearing age without effective contraception.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Prednisolone and Methotrexate (Control Arm); prednisolone 0.75mg/kg/day (a maximum dose of 30mg at baseline) and Methotrexate 15 mg weekly for 12 weeks.	Drug: Prednisolone; prednisolone 0.75mg/kg/day (a maximum dose of 30mg at baseline) orally; Drug: Methotrexate; Methotrexate 15 mg weekly orally
Experimental: Prednisolone and Apremilast (Test Arm); prednisolone 0.75mg/kg/day (a maximum dose of 30mg at baseline) and Apremilast 30 mg twice daily for 12 weeks.	Drug: Prednisolone; prednisolone 0.75mg/kg/day (a maximum dose of 30mg at baseline) orally; Drug: Apremilast; Apremilast 30 mg twice daily orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain by Visual Analogue Scale (VAS) score	Change in Visual Analogue Scale (VAS) score after treatment with prednisolone and methotraxate Vs Prednisolone and Apremilast at baseline, 8 weeks and 12 weeks. The VAS consists of a 10 cm line, with two endpoints representing 0 ('no pain') and 10 ('pain as bad as it could possibly be') interpretation of the scores: 0 =No Pain 2 = Mild 4 = Nagging 6 =Miserable 8 =Intense 10 = Worst	8 weeks and 12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Severity by Physician global assessment of disease (PGA) score	compare the proportion of patients achieving a reduction of Physician global assessment of disease (PGA) score of 0 or a 2-grade reduction (minimum initial PGA 3) after treatment with prednisolone and methotraxate Vs Prednisolone and Apremilast at baseline, 8 weeks and 12 weeks by using a 6-point disease severity scoring system. (0=clear, 1=almost clear, 2=mild, 3=moderate, 4=severe, 5=very severe).	8 weeks and 12 weeks
Severity and pain by oral mucosal disease severity score	the change in oral mucosal disease severity score (maximum 106) after treatment with prednisolone and methotraxate Vs Prednisolone and Apremilast at baseline, 8 weeks and 12 weeks. Total score = Site score + Activity score + pain Score (Maximum 106) higher scores indicating greater disease activity	8 weeks and 12 weeks
serum IL 6 level	Change in serum IL 6 after treatment with prednisolone and methotraxate Vs Prednisolone and Apremilast he levels of salivary and serum IL-6 were significantly higher among patients with OLP than among healthy control participants	12 weeks
Quality of life by using oral health-related quality of life score (ORAL HEALTH IMPACT PROFILE - 14 )	Change in the oral health-related quality of life from baseline after 8 and 12 weeks. designed to assess patients' perception of the impact of oral disorders on their quality of life (QoL). The OHIP-14 scores can range from 0 to 56 and are calculated by summing the ordinal values for the 14 items. The domain scores can range from 0 to 8. Higher OHIP-14 scores indicate worse and lower scores indicate better OHRQol	8 weeks and 12 weeks
Incidence of treatment-emergent adverse events of both test and control group	treatment-emergent adverse events in both the groups The adverse events in the patients are to be assessed by non-directive questioning at the time of the follow-up visit. Patients can access the investigators directly in case of any adverse events and report them. All adverse events irrespective of their previous reported status are to be recorded with details about nature, intensity, duration, measures taken, outcome, and causal relationship to prednisolone, methotrexate and apremilast.	12 weeks

Collaborators and Investigators

• Sponsor: All India Institute of Medical Sciences, Bhubaneswar
• Investigators: Study Director: Debasish Hota, MD, DM, professor

Publications and helpful links

General Publications

• Papp K, Reich K, Leonardi CL, Kircik L, Chimenti S, Langley RG, Hu C, Stevens RM, Day RM, Gordon KB, Korman NJ, Griffiths CE. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: Results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015 Jul;73(1):37-49. doi: 10.1016/j.jaad.2015.03.049.
• Farhi D, Dupin N. Pathophysiology, etiologic factors, and clinical management of oral lichen planus, part I: facts and controversies. Clin Dermatol. 2010 Jan-Feb;28(1):100-8. doi: 10.1016/j.clindermatol.2009.03.004.
• Gorouhi F, Davari P, Fazel N. Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis. ScientificWorldJournal. 2014 Jan 30;2014:742826. doi: 10.1155/2014/742826. eCollection 2014.
• Solimani F, Forchhammer S, Schloegl A, Ghoreschi K, Meier K. Lichen planus - a clinical guide. J Dtsch Dermatol Ges. 2021 Jun;19(6):864-882. doi: 10.1111/ddg.14565. Epub 2021 Jun 7.
• Veneri F, Bardellini E, Amadori F, Conti G, Majorana A. Efficacy of ozonized water for the treatment of erosive oral lichen planus: a randomized controlled study. Med Oral Patol Oral Cir Bucal. 2020 Sep 1;25(5):e675-e682. doi: 10.4317/medoral.23693.
• Le Cleach L, Chosidow O. Clinical practice. Lichen planus. N Engl J Med. 2012 Feb 23;366(8):723-32. doi: 10.1056/NEJMcp1103641. No abstract available.
• Mohan RPS, Gupta A, Kamarthi N, Malik S, Goel S, Gupta S. Incidence of Oral Lichen Planus in Perimenopausal Women: A Cross-sectional Study in Western Uttar Pradesh Population. J Midlife Health. 2017 Apr-Jun;8(2):70-74. doi: 10.4103/jmh.JMH_34_17.
• Kanwar AJ, De D. Methotrexate for treatment of lichen planus: old drug, new indication. J Eur Acad Dermatol Venereol. 2013 Mar;27(3):e410-3. doi: 10.1111/j.1468-3083.2012.04654.x. Epub 2012 Jul 24.
• Lajevardi V, Ghodsi SZ, Hallaji Z, Shafiei Z, Aghazadeh N, Akbari Z. Treatment of erosive oral lichen planus with methotrexate. J Dtsch Dermatol Ges. 2016 Mar;14(3):286-93. doi: 10.1111/ddg.12636.
• Chauhan P, De D, Handa S, Narang T, Saikia UN. A prospective observational study to compare efficacy of topical triamcinolone acetonide 0.1% oral paste, oral methotrexate, and a combination of topical triamcinolone acetonide 0.1% and oral methotrexate in moderate to severe oral lichen planus. Dermatol Ther. 2018 Jan;31(1). doi: 10.1111/dth.12563. Epub 2017 Nov 10.

Study record dates

Study Major Dates

• Study Start (Estimated): February 26, 2024
• Primary Completion (Estimated): January 31, 2025
• Study Completion (Estimated): May 31, 2025

Study Registration Dates

• First Submitted: January 25, 2024
• First Submitted That Met QC Criteria: February 13, 2024
• First Posted (Estimated): February 15, 2024

Study Record Updates

• Last Update Posted (Estimated): February 15, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: Methotrexate; VAS; Apremilast; Prednisolone; PGA; Oral lichen planus; Lichen planus; IL 6
• Additional Relevant MeSH Terms: Skin Diseases; Stomatognathic Diseases; Mouth Diseases; Skin Diseases, Papulosquamous; Lichenoid Eruptions; Lichen Planus, Oral; Lichen Planus; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dermatologic Agents; Reproductive Control Agents; Phosphodiesterase Inhibitors; Abortifacient Agents, Nonsteroidal; Abortifacient Agents; Folic Acid Antagonists; Phosphodiesterase 4 Inhibitors; Prednisolone; Methotrexate; Apremilast
• Other Study ID Numbers: AIIMS BBSR/PGThesis/23-24/112

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No