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Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum (MaPs)

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ClinicalTrials.gov Identifier: NCT03775460
Recruitment Status : Not yet recruiting
First Posted : December 14, 2018
Last Update Posted : August 13, 2019
Sponsor:
Collaborators:
Dr. Soetomo General Hospital
The Leprosy Mission Trust, India
Alert Hospital, Ethiopia
The Leprosy Mission Bangladesh
Bombay Leprosy Project, India
Oswaldo Cruz Foundation
Leprosy Research Initiative
The Leprosy Mission Nepal
Information provided by (Responsible Party):
London School of Hygiene and Tropical Medicine

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Erythema Nodosum Leprosum Drug: Methotrexate Drug: Placebo Drug: Prednisolone Not Applicable

Detailed 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.

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 550 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum (MaPS in ENL
Estimated Study Start Date : January 1, 2020
Estimated Primary Completion Date : April 1, 2022
Estimated Study Completion Date : April 1, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Placebo Comparator: control
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
Participants in the control arm will receive placebo along side prednisolone

Drug: Prednisolone
Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks
Experimental: intervention
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
Participants in the intervention group will receive methotrexate along side prednisolone

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


Outcome Measures
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Primary Outcome Measures :
  1. Proportion of individuals free from Erythema Nodosum Leprosum (ENL) flares in 24 weeks [ Time Frame: During the first 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.

  2. Proportion of individuals free from ENL flares in 48 weeks [ Time Frame: During first 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


Secondary Outcome Measures :
  1. Change in ENLIST ENL severity scale score (EESS) [ Time Frame: 60 weeks ]
    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

  2. Quality of life changes: 36- Item Short Form (SF-36) questionnaire [ Time Frame: at 24 and 48 weeks ]
    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.

  3. Quality of life changes regarding skin condition: Dermatology life quality Index (DLQI) [ Time Frame: at 24 and 48 weeks ]
    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.

  4. Proportion of individuals free from ENL flares at 60 weeks [ Time Frame: 60 weeks ]
    Proportion of individuals who do not require prednisolone at 60 weeks

  5. ENL flares per individual up to 60 weeks [ Time Frame: 60 weeks ]
    Number of flares of ENL per individual requiring additional prednisolone up to 60 weeks

  6. Severity of ENL flares [ Time Frame: 60 weeks ]
    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

  7. Time to the first flare of ENL [ Time Frame: 60 weeks ]
    How long it takes to a participant who has an ENL flare to present with first episode of flare after enrolment

  8. Adverse effects [ Time Frame: 60 weeks ]
    Proportion of individuals with treatment related adverse effects

  9. Quality of life at 60 weeks: SF-36 questionnaire [ Time Frame: 60 weeks ]
    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

  10. Quality of life at 60 weeks regarding skin condition: Dermatology Life Quality Index (DLQI) questionnaires [ Time Frame: 60 weeks ]
    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.

  11. Individuals free from ENL flares in 60 weeks [ Time Frame: 60 weeks ]
    Proportion of individuals who have not required additional prednisolone in the 60 weeks of the trial


Eligibility Criteria
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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03775460


Contacts
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Contact: Barbara de Barros, M.D +44(0)2079272316 barbara.de-barros@lshtm.ac.uk

Locations
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Bangladesh
TMLI Bangladesh/ DBLM hospital Not yet recruiting
Dhaka, Bangladesh
Contact: Benjamin Jewel Rozario         
Brazil
FIOCRUZ Not yet recruiting
Rio De Janeiro, Brazil
Contact: Jose' Nery         
Ethiopia
ALERT Not yet recruiting
Addis Ababa, Ethiopia
Contact: Saba Lambert         
India
The Leprosy Mission Trust Not yet recruiting
Delhi, India
Contact: Joydeepa Darlong         
Bombay Leprosy Project Not yet recruiting
Mumbai, India
Contact: Vivek Pai         
Indonesia
Soetomo Hospital Not yet recruiting
Surabaya, Indonesia
Contact: Medhi Alinda         
Nepal
Anandaban Hospital Not yet recruiting
Kathmandu, Nepal
Contact: Deanna Hagge         
Sponsors and Collaborators
London School of Hygiene and Tropical Medicine
Dr. Soetomo General Hospital
The Leprosy Mission Trust, India
Alert Hospital, Ethiopia
The Leprosy Mission Bangladesh
Bombay Leprosy Project, India
Oswaldo Cruz Foundation
Leprosy Research Initiative
The Leprosy Mission Nepal
Investigators
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Principal Investigator: Stephen Walker, MD, PhD London School of Hygiene and Tropical Medicine
More Information
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Publications:

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Responsible Party: London School of Hygiene and Tropical Medicine
ClinicalTrials.gov Identifier: NCT03775460     History of Changes
Other Study ID Numbers: 15762
First Posted: December 14, 2018    Key Record Dates
Last Update Posted: August 13, 2019
Last Verified: November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by London School of Hygiene and Tropical Medicine:
Erythema Nodosum Leprosum
ENL
corticosteroids
Methotrexate
 ENL severity scale
quality of life
Leprosy
Additional relevant MeSH terms:
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Prednisolone
Methylprednisolone Acetate
Methylprednisolone
Methylprednisolone Hemisuccinate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Erythema
Erythema Nodosum
Skin Diseases
Skin Manifestations
Signs and Symptoms
Drug Eruptions
Dermatitis
Drug Hypersensitivity
 Hypersensitivity
Immune System Diseases
Drug-Related Side Effects and Adverse Reactions
Chemically-Induced Disorders
Methotrexate
Abortifacient Agents, Nonsteroidal
Abortifacient Agents
Reproductive Control Agents
Physiological Effects of Drugs
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Dermatologic Agents
Enzyme Inhibitors