A Study to Evaluate the Efficacy and Safety of Apremilast in Patients of Chronic and Recurrent Erythema Nodosum Leprosum

NCT04822909 | Completed Phase 4

• 1 other identifier: NK/4917/Study/05
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 3

Brief Summary

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. The disease manifests with a varied spectrum, ranging from localized tuberculoid leprosy (TT) to generalized lepromatous leprosy (LL) types. The normal course of leprosy is interrupted by troublesome immune reactions, namely lepra reactions. ENL (a type 2 lepra reaction) is an immune-mediated hypersensitivity reaction, presenting as erythematous, tender, papulo-nodules and associated with constitutional symptoms (fever, arthralgias etc). Pro-inflammatory mediators are elevated, especially tumour necrosis factor α (TNF-α), interferon-γ (IFN- γ) and interleukins (IL-2, IL-6, IL-12). LL type and high bacteriological index are considered to be risk factors for ENL. Lesions usually appear after starting MDT, although it may also be presenting feature. Diagnosis is made by characteristic lesions associated with constitutional symptoms and painful nerve thickening. Mild episodes of ENL respond to adequate rest and oral aspirin. Severe episodes necessitate anti-inflammatory drugs like corticosteroids (e.g. Prednisolone) and/or thalidomide. Use of high-dose prednisolone increases risk of steroid toxicity. Thalidomide is category X drug (unsafe in pregnancy), not freely available and has cost-limitations. Clofazimine requires higher doses, takes 4 to 6 weeks to be effective and produces gastrointestinal side-effects and skin discoloration. Minocycline has been tried as an alternative; however the drug itself has been reported to precipitate ENL in some patients. Thus, a safe and effective steroid-sparing agent for ENL remains elusive. Cyclic adenosine monophosphate (cAMP) is an intracellular signal molecule. Phosphodiesterases (PDEs) catalyse degradation of cAMP leading to its inactivation. Inhibition of PDEs leads to increased intracellular cAMP, which has anti-inflammatory actions. PDE-4 isoenzymes are the predominant cAMP degrading enzymes in most immune cells. Apremilast is an oral phosphodiesterase-4 (PDE-4) inhibitor currently used clinically for the treatment of psoriasis and other chronic inflammatory diseases. The anti-inflammatory effects of apremilast shown in-vitro includes downregulating TNF-α, IFN-γ, IL-2, IL-12 and IL-23. Although apremilast is not yet clinically indicated in ENL, its anti-inflammatory spectrum targeting the same molecules as those implicated in ENL and efficacy seen in other inflammatory conditions warrants its trial in chronic, recurrent ENL patients.

Conditions

Erythema Nodosum Leprosum

Outcome Measures

Primary Outcomes (1)

• Efficacy of apremilast in chronic, recurrent erythema nodosum leprosum

  Duration taken to attain clinical remission shall be determined in patients with chronic, recurrent erythema nodosum leprosum receiving apremilast

  6 months

Secondary Outcomes (2)

• Clinical features of ENL

  6 months

• Adverse effects of apremilast

  6 months

Study Arms (1)

Apremilast group

EXPERIMENTAL

The study patients will be treated with oral apremilast, administered initially a dose of 10 mg once daily, gradually increasing to reach the maximal therapeutic dosage of 30 mg twice daily before end of 1st week of starting the therapy. The treatment will be continued till 6 months and we will taper the steroids by 10mg/ 2 weeks till 20mg and then 5 mg/ 2 weeks till discontinuation of steroids.

Drug: Apremilast;Apremilast;Apremilast 10 MG; 20 MG; 30 MG Oral Tablet

Interventions

Apremilast;Apremilast;Apremilast 10 MG; 20 MG; 30 MG Oral Tablet DRUG

The study patients will be treated with oral apremilast, administered initially a dose of 10 mg once daily, gradually increasing to reach the maximal therapeutic dosage of 30 mg twice daily before end of 1st week of starting the therapy. The treatment will be continued till 6 months and we will taper the steroids by 10mg/ 2 weeks till 20mg and then 5 mg/ 2 weeks till discontinuation of steroids. If a patient worsens after treatment or develops any serious adverse event after initiation of treatment, he will be withdrawn from the study. If there is no response to the treatment and we are unable to taper steroids after 12 weeks of therapy then the patient will be withdrawn from the study

Also known as: Apremilast

Apremilast group

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Chronic and recurrent ENL cases of leprosy regardless of age, sex and treatment status with MDT
• Patients not responded with paracetamol, clofazimine, pentoxifylline, colchicine, methotrexate, azathioprine, TNF inhibitors etc.,
• Patients who can give valid consent.
• Willing for monthly follow-up visits for at least 3 months.

You may not qualify if:

• Pregnant and lactating mothers
• Severe renal dysfunction
• Patients with HIV, Hepatitis B and Hepatitis C
• Inability to come for monthly follow up visits for 6 months
• Those who cannot provide consent for the study
• Known case of psychiatric disease

Sponsors & Collaborators

• Post Graduate Institute of Medical Education and Research, Chandigarh: lead

Study Sites (3)

Dermatology OPD, New OPD Building, Level 5C, Postgraduate Institute of Medical Education and Research

Chandigarh, 160012, India

Location

PGIMER

Chandigarh, 160012, India

Location

Tarun Narang

Chandigarh, 160012, India

Location

Related Publications (10)

• Parkash O. Classification of leprosy into multibacillary and paucibacillary groups: an analysis. FEMS Immunol Med Microbiol. 2009 Jan;55(1):1-5. doi: 10.1111/j.1574-695X.2008.00491.x. Epub 2008 Nov 13.

  PMID: 19040664 BACKGROUND

• Ridley DS, Jopling WH. Classification of leprosy according to immunity. A five-group system. Int J Lepr Other Mycobact Dis. 1966 Jul-Sep;34(3):255-73. No abstract available.

  PMID: 5950347 BACKGROUND

• Lockwood DN, Nicholls P, Smith WC, Das L, Barkataki P, van Brakel W, Suneetha S. Comparing the clinical and histological diagnosis of leprosy and leprosy reactions in the INFIR cohort of Indian patients with multibacillary leprosy. PLoS Negl Trop Dis. 2012;6(6):e1702. doi: 10.1371/journal.pntd.0001702. Epub 2012 Jun 26.

  PMID: 22745841 BACKGROUND

• Partida-Sanchez S, Favila-Castillo L, Pedraza-Sanchez S, Gomez-Melgar M, Saul A, Estrada-Parra S, Estrada-Garcia I. IgG antibody subclasses, tumor necrosis factor and IFN-gamma levels in patients with type II lepra reaction on thalidomide treatment. Int Arch Allergy Immunol. 1998 May;116(1):60-6. doi: 10.1159/000023926.

  PMID: 9623511 BACKGROUND

• Van Veen NH, Lockwood DN, van Brakel WH, Ramirez J Jr, Richardus JH. Interventions for erythema nodosum leprosum. Cochrane Database Syst Rev. 2009 Jul 8;2009(3):CD006949. doi: 10.1002/14651858.CD006949.pub2.

  PMID: 19588412 BACKGROUND

• Schafer PH, Parton A, Gandhi AK, Capone L, Adams M, Wu L, Bartlett JB, Loveland MA, Gilhar A, Cheung YF, Baillie GS, Houslay MD, Man HW, Muller GW, Stirling DI. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010 Feb;159(4):842-55. doi: 10.1111/j.1476-5381.2009.00559.x. Epub 2009 Dec 24.

  PMID: 20050849 BACKGROUND

• Papp K, Cather JC, Rosoph L, Sofen H, Langley RG, Matheson RT, Hu C, Day RM. Efficacy of apremilast in the treatment of moderate to severe psoriasis: a randomised controlled trial. Lancet. 2012 Aug 25;380(9843):738-46. doi: 10.1016/S0140-6736(12)60642-4. Epub 2012 Jun 29.

  PMID: 22748702 BACKGROUND

• Kavanaugh A, Mease PJ, Gomez-Reino JJ, Adebajo AO, Wollenhaupt J, Gladman DD, Hochfeld M, Teng LL, Schett G, Lespessailles E, Hall S. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015 Mar;42(3):479-88. doi: 10.3899/jrheum.140647. Epub 2015 Jan 15.

  PMID: 25593233 BACKGROUND

• Crowley J, Thaci D, Joly P, Peris K, Papp KA, Goncalves J, Day RM, Chen R, Shah K, Ferrandiz C, Cather JC. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for >/=156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017 Aug;77(2):310-317.e1. doi: 10.1016/j.jaad.2017.01.052. Epub 2017 Apr 14.

  PMID: 28416342 BACKGROUND

• Walker SL, Sales AM, Butlin CR, Shah M, Maghanoy A, Lambert SM, Darlong J, Rozario BJ, Pai VV, Balagon M, Doni SN, Hagge DA, Nery JAC, Neupane KD, Baral S, Sangma BA, Alembo DT, Yetaye AM, Hassan BA, Shelemo MB, Nicholls PG, Lockwood DNJ; Erythema Nodosum Leprosum International STudy Group. A leprosy clinical severity scale for erythema nodosum leprosum: An international, multicentre validation study of the ENLIST ENL Severity Scale. PLoS Negl Trop Dis. 2017 Jul 3;11(7):e0005716. doi: 10.1371/journal.pntd.0005716. eCollection 2017 Jul.

  PMID: 28671966 BACKGROUND

MeSH Terms

Interventions

Tablets; apremilast

Intervention Hierarchy (Ancestors)

Dosage Forms; Pharmaceutical Preparations

Study Officials

• Tarun Narang, MD

  Post Graduate Institute of Medical Education and Research, Chandigarh

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Assistant Professor

Study Record Dates

• First Submitted: March 26, 2021
• First Posted: March 30, 2021
• Study Start: September 15, 2019
• Primary Completion: March 14, 2020
• Study Completion: June 30, 2020
• Last Updated: March 30, 2021

Record last verified: 2021-03

Data Sharing

• IPD Sharing: Will not share

Locations

IN (3)