A Pilot Study to Evaluate the Efficacy and Safety of Apremilast in Patients of Chronic and Recurrent Erythema Nodosum Leprosum
Trial Snapshot
- Phase
- Phase 4
- Status
- Completed
- Sponsor
- Enrollment
- 10
- Locations
- 3
- Primary Endpoint
- Efficacy of apremilast in chronic, recurrent erythema nodosum leprosum
Study Overview
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.
Detailed Description
ENL is confined to leprosy patients classified as BL or LL (Ridley-Jopling), which in turn comprise the multi-bacillary (MB) patient group, as defined by WHO. ENL presents as new, red, painful and tender nodules in the skin, usually on the legs and arms, and sometimes on the trunk. ENL varies in severity. When the reaction is mild, only the skin is affected and there may be low grade fever. When the reaction is severe, the nodules are multiple and may ulcerate, and other organs may be inflamed, such as the nerves, eyes, joints, testes, and lymph nodes. ENL may occur before, during or after MDT treatment, and several years later. It can occur as a single acute episode, but frequently develops into a chronic condition with recurrent episodes. Immune responses causing ENL are triggered by high loads of fragmented bacilli in skin tissue. The complex mechanisms underlying ENL are not fully understood yet which makes treatment difficult.
Treatment of ENL is much debated and a very challenging issue. There is no universally accepted regimen that is fully effective. Most therapies for ENL aim to control the acute inflammation, relieving the pain and preventing further damage or new episodes. Several treatments are available for ENL. The conventional treatment for mild ENL is rest and anti-inflammatory medication. Aspirin was the most commonly used anti-inflammatory medication, but indomethacin, chloroquine and colchicine have been tested as well. There is not much evidence that these drugs are more beneficial than aspirin. For severe ENL, prednisolone, the most widely available corticosteroid, and clofazimine are most commonly used. ENL is often recurrent or chronic and requires high-dose and prolonged courses of prednisolone for disease control. This increases the risk of adverse events, such as hypertension or diabetes, and steroid dependency.
Apremilast is a novel, phosphodiesterase 4 (PDE 4) antagonist, and an orally administered small molecule, acts by specifically targeting a central pathogenic mechanism, binding directly to the PDE-4 enzyme and evading complex antigen-receptor interactive immunoregulatory mechanisms. Apremilast is an immune modulator rather than an immunosuppressant.
Anti-inflammatory actions of Apremilast includes
- Increased levels of cAMP, which reduces the levels of pro- inflammatory cytokines (such as tumor necrosis factor (TNF)-α, interleukin (IL)-23, IL-12, and leukotriene B4) and also increases the levels of anti-inflammatory cytokines (such as IL-10)
- Binds to toll-like receptor 4 in peripheral blood mononuclear cells, which further decrease the production of pro-inflammatory cytokines
- Decreases the activity of nitric oxide synthase Because of its anti-inflammatory actions, Apremilast may have a significant role in the treatment of patients with Erythema Nodosum Leprosum who have not responded to other conventional treatment.
Study Design
- Study Type
- Interventional
- Allocation
- Na
- Intervention Model
- Single Group
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •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.
Exclusion Criteria
- •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
Arms & Interventions
Apremilast group
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.
Intervention: Apremilast;Apremilast;Apremilast 10 MG; 20 MG; 30 MG Oral Tablet (Drug)
Outcomes
Primary Outcomes
Efficacy of apremilast in chronic, recurrent erythema nodosum leprosum
Time Frame: 6 months
Duration taken to attain clinical remission shall be determined in patients with chronic, recurrent erythema nodosum leprosum receiving apremilast
Secondary Outcomes
- Clinical features of ENL(6 months)
- Adverse effects of apremilast(6 months)
Investigators
Dr. Tarun Narang
Assistant Professor
Post Graduate Institute of Medical Education and Research, Chandigarh