Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum (MaPs)

London School of Hygiene and Tropical Medicine

Status: Enrolling

Conditions: Erythema Nodosum Leprosum

Treatments: Drug: Prednisolone; Drug: Methotrexate; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT03775460

15762

Details and patient eligibility

About

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.

Full description

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.

Enrollment: 550 estimated patients

Sex: All

Ages: 18 to 60 years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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550 participants in 2 patient groups, including a placebo group

control

Placebo Comparator group

Description:

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.

Treatment:

Drug: Placebo

Drug: Prednisolone

intervention

Experimental group

Description:

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.

Treatment:

Drug: Methotrexate

Drug: Prednisolone