Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum

N/AActive Not RecruitingNCT03775460

London School of Hygiene and Tropical Medicine550 enrolled

Overview

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.

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.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

QUADRUPLE

Enrollment

550

Conditions

Erythema Nodosum Leprosum

Interventions

MethotrexateDRUG

Participants in the intervention group will receive methotrexate along side prednisolone

PlaceboDRUG

Participants in the control arm will receive placebo along side prednisolone

PrednisoloneDRUG

Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks

Eligibility

Sex: ALLMin age: 18 YearsMax age: 60 Years

Medical Language ↔ Plain English

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): 1. Individuals who diagnosed with leprosy complicated by ENL 2. Individuals with ENL aged 18-60 years old 3. Individuals with ENL deteriorating symptoms 4. Individuals with 10 or more tender, papular or nodular ENL skin lesions 5. Individuals with an EESS score of at least 9 6. Individuals with ENL on: 1. No current anti- ENL treatment 2. Prednisolone up to 30mg per day (if ACUTE) or Prednisolone 10-30mg (inclusive) per day (if RECURRENT/ CHRONIC) or equivalent alternative corticosteroid dose OR 3. Thalidomide or other non-steroidal anti-ENL medication OR 4. A combination of prednisolone (up to 30mg) and another non-steroidal anti-ENL medication (thalidomide, clofazimine, azathioprine, pentoxifylline, ciclosporin, minocycline) Exclusion criteria: 1. Individuals who were first diagnosed with ENL more than 4 years prior to enrolment 2. Individuals less than 18 years old or older than 60 years 3. Individuals weighing less than 35kg 4. Individuals with 9 or fewer tender, popular or nodular ENL skin lesions 5. Individuals with an EESS score of 8 or less 6. 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 7. Pregnant or breastfeeding women 8. Individuals with recurrent or chronic ENL who deteriorate on a dose of prednisolone less than 10 mg or more than 30 mg 9. Individuals who have taken methotrexate by any route for the last 12 weeks 10. Individuals with a hypersensitivity to methotrexate or a recognised contraindication ( please see Methotrexate information sheet) 11. Individuals currently diagnosed with Type 1 reaction or Lucio's phenomenon 12. Individuals with the severe abnormalities in screening investigations 13. Positive serology for HIV, Hepatitis B or C 14. Evidence of tuberculosis or pulmonary fibrosis 15. A history of chronic liver disease or excessive alcohol or illicit substance consumption 16. Individuals with severe inter-current infections, uncontrolled diabetes, active peptic ulcer disease, untreated malignancy 17. Individuals unable to attend regularly for assessment or monitoring

Locations (7)

TMLI Bangladesh/ DBLM hospital

Dhaka, Bangladesh

FIOCRUZ

Rio de Janeiro, Brazil

ALERT

Addis Ababa, Ethiopia

The Leprosy Mission Trust

Delhi, India

Outcomes

Primary Outcomes

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.

Time frame: 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

Time frame: During first 48 weeks

Secondary Outcomes

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

Time frame: 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.

Time frame: at 24 and 48 weeks

Data from ClinicalTrials.gov

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