Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum

Study Overview
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Brief Summary
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Erythema Nodosum Leprosum (ENL) is a painful, debilitating complication of leprosy. Patients often require high doses of corticosteroids for prolonged periods. Thalidomide is expensive and not available in most countries. The use of corticosteroids for long periods is associated with adverse effects and mortality. It is a priority to identify alternative agents to treat ENL. Methotrexate (MTX) is a cheap, widely used medication which has been reported to be effective in ENL resistant to steroids and thalidomide.

Detailed Description
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This is a double blind randomized controlled trial (RCT) to test the efficacy of MTX for managing ENL. Patients diagnosed with moderate or severe ENL at ENLIST Group centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal will be randomly allocated to receive a 15 or 20 mg of oral MTX each week for 48 weeks and prednisolone 40 mg per day reducing to zero over 20 weeks. The control group will receive an identical prednisolone scheme. The participants will be stratified into two groups, those with acute ENL, those with chronic/recurrent ENL. The interventions for both populations are the same, although analysed separately. Adverse effects (AE) will be closely monitored clinically and using laboratory tests. Participants will receive folic acid, 5mg daily for 52 weeks except on the day of MTX to prevent AEs, and nausea will be managed with ondansetron.

Official Title
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Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum (MaPS in ENL

Conditions
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Erythema Nodosum Leprosum

Intervention / Treatment
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* Drug: Methotrexate
* Drug: Placebo
* Drug: Prednisolone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria:: ALL OF THE FOLLOWING SIX CRITERIA MUST BE MET IN ORDER FOR AN INDIVIDUAL TO BE ELIGIBLE (ONLY ONE OF 6A TO 6D NEED BE MET): Individuals who diagnosed with leprosy complicated by ENL Individuals with ENL aged 18-60 years old Individuals with ENL deteriorating symptoms Individuals with 10 or more tender, papular or nodular ENL skin lesions Individuals with an EESS score of at least 9 Individuals with ENL on: No current anti- ENL treatment Prednisolone up to 30mg per day (if ACUTE) or Prednisolone 10-30mg (inclusive) per day (if RECURRENT/ CHRONIC) or equivalent alternative corticosteroid dose OR Thalidomide or other non-steroidal anti-ENL medication OR A combination of prednisolone (up to 30mg) and another non-steroidal anti-ENL medication (thalidomide, clofazimine, azathioprine, pentoxifylline, ciclosporin, minocycline) Exclusion criteria: Individuals who were first diagnosed with ENL more than 4 years prior to enrolment Individuals less than 18 years old or older than 60 years Individuals weighing less than 35kg Individuals with 9 or fewer tender, popular or nodular ENL skin lesions Individuals with an EESS score of 8 or less Women of child bearing capacity who decline to use two forms of adequate contraception and men who decline to use two forms of adequate contraception Pregnant or breastfeeding women Individuals with recurrent or chronic ENL who deteriorate on a dose of prednisolone less than 10 mg or more than 30 mg Individuals who have taken methotrexate by any route for the last 12 weeks Individuals with a hypersensitivity to methotrexate or a recognised contraindication ( please see Methotrexate information sheet) Individuals currently diagnosed with Type 1 reaction or Lucio's phenomenon Individuals with the severe abnormalities in screening investigations Positive serology for HIV, Hepatitis B or C Evidence of tuberculosis or pulmonary fibrosis A history of chronic liver disease or excessive alcohol or illicit substance consumption Individuals with severe inter-current infections, uncontrolled diabetes, active peptic ulcer disease, untreated malignancy Individuals unable to attend regularly for assessment or monitoring

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: control<br>Participants will receive placebo+ prednisolone. Participants will start receiving 4 dummy tablets per week, than participants weighing less than 60 kg will receive 6 dummy tablets from week 8. The placebo will be prescribe weekly. Participants weighing 60 kg or more will receive 8 dummy tablets from week 8. Participants will receive dummy tablets for 52 weeks. Along with prednisolone. The start dose of prednisolone will be 40 mg per day decreasing dosage for 20 weeks. | Drug: Placebo<br>* Participants in the control arm will receive placebo along side prednisolone<br>Drug: Prednisolone<br>* Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks<br>|
| Experimental: intervention<br>Participants will receive Methotrexate(MTX)+prednisolone. All participants in intervention arm will receive an initial dose of MTX 10 mg. The MTX will be increased to 15 mg the following week. Participants weighing less than 60 kg will continue to receive 15 mg of MTX weekly thereafter. Individuals weighing 60 kg or more will receive MTX 20 mg from week 8. At week 48 the MTX will be reduced to 10 mg for two weeks followed by 5 mg for two weeks and then stopped. In total participants will receive 52 weeks of MTX along side prednisolone, which will be the same as the control arm. | Drug: Methotrexate<br>* Participants in the intervention group will receive methotrexate along side prednisolone<br>Drug: Prednisolone<br>* Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of individuals free from Erythema Nodosum Leprosum (ENL) flares in 24 weeks | Proportion of individuals who have not required additional prednisolone during the first 24 weeks. The aim is to evaluate if individuals in the methotrexate regimen will need less prednisolone than the control arm. | During the first 24 weeks | 
| Proportion of individuals free from ENL flares in 48 weeks | Proportion of individuals who have not required additional prednisolone during the first 48 weeks. To evaluate if methotrexate will be more efficient to control ENL than only prednisolone | During first 48 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in ENLIST ENL severity scale score (EESS) | ENLIST group (Erythema Nodosum Leprosum International STudy) developed and validated a severity scale for ENL, which consist 10 symptoms and signs of ENL and range from 0 to 30 points. Mild ENL is categorised as an score of 8 or less. We will measure the change in ENLIST ENL Severity Scale score from baseline to the first flare of ENL requiring additional prednisolone | 60 weeks | 
| Quality of life changes: 36- Item Short Form (SF-36) questionnaire | Change in patient reported health-related quality of life at 24 and 48 weeks from baseline. This will be measured by 36- Item Short Form (SF-36) questionnaire developed by RAND, validated worldwide. The SF-36 consists of 8 scaled scores, which are the weighted sums of the questions in their section. Each scale is directly transformed into a 0-100 scale. The lower the score the more disability. If the score is 0 is equivalent to maximum disability. The 8 sections are vitality, physical functioning, bodily pain, general health perceptions, physical role functioning, emotional role functioning, emotional role functioning, social role functioning and mental health. | at 24 and 48 weeks | 
| Quality of life changes regarding skin condition: Dermatology life quality Index (DLQI) | Change in patient reported health-related quality of life at 24 and 48 weeks, specific to skin condition, such as ENL. It will be used the Dermatology life quality Index (DLQI),which is a questionnaire of 10 questions to specific evaluate quality of life in dermatologic conditions.The score can range from 0 to 30, meaning 0 no effect at all on patient's life to 30 extremely large effect on patient's life. | at 24 and 48 weeks | 
| Proportion of individuals free from ENL flares at 60 weeks | Proportion of individuals who do not require prednisolone at 60 weeks | 60 weeks | 
| ENL flares per individual up to 60 weeks | Number of flares of ENL per individual requiring additional prednisolone up to 60 weeks | 60 weeks | 
| Severity of ENL flares | As stated on outcome 3, the severity of ENL will be measured by ENLIST ENL severity scale. The scale is composed by 10 symptoms and signs of ENL and range from 0 to 30 points. Mild ENL is categorised as an score of 8 or less. We will measure the maximum severity of flares of ENL requiring additional prednisolone up to 60 weeks | 60 weeks | 
| Time to the first flare of ENL | How long it takes to a participant who has an ENL flare to present with first episode of flare after enrolment | 60 weeks | 
| Adverse effects | Proportion of individuals with treatment related adverse effects | 60 weeks | 
| Quality of life at 60 weeks: SF-36 questionnaire | As described on outcome 4. We will use SF-36 questionnaire to measure quality of life. Change in patient reported health-related quality of life at 60 weeks from baseline | 60 weeks | 
| Quality of life at 60 weeks regarding skin condition: Dermatology Life Quality Index (DLQI) questionnaires | As described on outcome 5. We will use DLQI questionnaires to measure quality of life. Change in patient reported health-related quality of life at 60 weeks from baseline, specific to skin conditions such as ENL. | 60 weeks | 
| Individuals free from ENL flares in 60 weeks | Proportion of individuals who have not required additional prednisolone in the 60 weeks of the trial | 60 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Erythema Nodosum Leprosum, ENL, corticosteroids, Methotrexate, ENL severity scale, quality of life, Leprosy