<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03775460</url>
  </required_header>
  <id_info>
    <org_study_id>15762</org_study_id>
    <nct_id>NCT03775460</nct_id>
  </id_info>
  <brief_title>Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum</brief_title>
  <acronym>MaPs</acronym>
  <official_title>Methotrexate and Prednisolone Study in Erythema Nodosum Leprosum (MaPS in ENL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>London School of Hygiene and Tropical Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Dr. Soetomo General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leprosy Mission Trust, India</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Alert Hospital, Ethiopia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leprosy Mission Bangladesh</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Bombay Leprosy Project, India</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Oswaldo Cruz Foundation</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Leprosy Research Initiative</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>The Leprosy Mission Nepal</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>London School of Hygiene and Tropical Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      Erythema Nodosum Leprosum (ENL) is a painful, debilitating complication of leprosy. Patients&#xD;
      often require high doses of corticosteroids for prolonged periods. Thalidomide is expensive&#xD;
      and not available in most countries. The use of corticosteroids for long periods is&#xD;
      associated with adverse effects and mortality. It is a priority to identify alternative&#xD;
      agents to treat ENL. Methotrexate (MTX) is a cheap, widely used medication which has been&#xD;
      reported to be effective in ENL resistant to steroids and thalidomide.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This is a double blind randomized controlled trial (RCT) to test the efficacy of MTX for&#xD;
      managing ENL. Patients diagnosed with moderate or severe ENL at ENLIST Group centres in&#xD;
      Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal will be randomly allocated to&#xD;
      receive a 15 or 20 mg of oral MTX each week for 48 weeks and prednisolone 40 mg per day&#xD;
      reducing to zero over 20 weeks. The control group will receive an identical prednisolone&#xD;
      scheme. The participants will be stratified into two groups, those with acute ENL, those with&#xD;
      chronic/recurrent ENL. The interventions for both populations are the same, although analysed&#xD;
      separately. Adverse effects (AE) will be closely monitored clinically and using laboratory&#xD;
      tests. Participants will receive folic acid, 5mg daily for 52 weeks except on the day of MTX&#xD;
      to prevent AEs, and nausea will be managed with ondansetron.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 15, 2023</start_date>
  <completion_date type="Anticipated">December 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Proportion of individuals free from Erythema Nodosum Leprosum (ENL) flares in 24 weeks</measure>
    <time_frame>During the first 24 weeks</time_frame>
    <description>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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Proportion of individuals free from ENL flares in 48 weeks</measure>
    <time_frame>During first 48 weeks</time_frame>
    <description>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</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in ENLIST ENL severity scale score (EESS)</measure>
    <time_frame>60 weeks</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life changes: 36- Item Short Form (SF-36) questionnaire</measure>
    <time_frame>at 24 and 48 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life changes regarding skin condition: Dermatology life quality Index (DLQI)</measure>
    <time_frame>at 24 and 48 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Proportion of individuals free from ENL flares at 60 weeks</measure>
    <time_frame>60 weeks</time_frame>
    <description>Proportion of individuals who do not require prednisolone at 60 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>ENL flares per individual up to 60 weeks</measure>
    <time_frame>60 weeks</time_frame>
    <description>Number of flares of ENL per individual requiring additional prednisolone up to 60 weeks</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Severity of ENL flares</measure>
    <time_frame>60 weeks</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to the first flare of ENL</measure>
    <time_frame>60 weeks</time_frame>
    <description>How long it takes to a participant who has an ENL flare to present with first episode of flare after enrolment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse effects</measure>
    <time_frame>60 weeks</time_frame>
    <description>Proportion of individuals with treatment related adverse effects</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life at 60 weeks: SF-36 questionnaire</measure>
    <time_frame>60 weeks</time_frame>
    <description>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</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life at 60 weeks regarding skin condition: Dermatology Life Quality Index (DLQI) questionnaires</measure>
    <time_frame>60 weeks</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Individuals free from ENL flares in 60 weeks</measure>
    <time_frame>60 weeks</time_frame>
    <description>Proportion of individuals who have not required additional prednisolone in the 60 weeks of the trial</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">550</enrollment>
  <condition>Erythema Nodosum Leprosum</condition>
  <arm_group>
    <arm_group_label>control</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <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.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methotrexate</intervention_name>
    <description>Participants in the intervention group will receive methotrexate along side prednisolone</description>
    <arm_group_label>intervention</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Participants in the control arm will receive placebo along side prednisolone</description>
    <arm_group_label>control</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone</intervention_name>
    <description>Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks</description>
    <arm_group_label>control</arm_group_label>
    <arm_group_label>intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:: ALL OF THE FOLLOWING SIX CRITERIA MUST BE MET IN ORDER FOR AN&#xD;
        INDIVIDUAL TO BE ELIGIBLE (ONLY ONE OF 6A TO 6D NEED BE MET):&#xD;
&#xD;
          1. Individuals who diagnosed with leprosy complicated by ENL&#xD;
&#xD;
          2. Individuals with ENL aged 18-60 years old&#xD;
&#xD;
          3. Individuals with ENL deteriorating symptoms&#xD;
&#xD;
          4. Individuals with 10 or more tender, papular or nodular ENL skin lesions&#xD;
&#xD;
          5. Individuals with an EESS score of at least 9&#xD;
&#xD;
          6. Individuals with ENL on:&#xD;
&#xD;
               1. No current anti- ENL treatment&#xD;
&#xD;
               2. Prednisolone up to 30mg per day (if ACUTE) or Prednisolone 10-30mg (inclusive)&#xD;
                  per day (if RECURRENT/ CHRONIC) or equivalent alternative corticosteroid dose OR&#xD;
&#xD;
               3. Thalidomide or other non-steroidal anti-ENL medication OR&#xD;
&#xD;
               4. A combination of prednisolone (up to 30mg) and another non-steroidal anti-ENL&#xD;
                  medication (thalidomide, clofazimine, azathioprine, pentoxifylline, ciclosporin,&#xD;
                  minocycline)&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Individuals who were first diagnosed with ENL more than 4 years prior to enrolment&#xD;
&#xD;
          2. Individuals less than 18 years old or older than 60 years&#xD;
&#xD;
          3. Individuals weighing less than 35kg&#xD;
&#xD;
          4. Individuals with 9 or fewer tender, popular or nodular ENL skin lesions&#xD;
&#xD;
          5. Individuals with an EESS score of 8 or less&#xD;
&#xD;
          6. Women of child bearing capacity who decline to use two forms of adequate contraception&#xD;
             and men who decline to use two forms of adequate contraception&#xD;
&#xD;
          7. Pregnant or breastfeeding women&#xD;
&#xD;
          8. Individuals with recurrent or chronic ENL who deteriorate on a dose of prednisolone&#xD;
             less than 10 mg or more than 30 mg&#xD;
&#xD;
          9. Individuals who have taken methotrexate by any route for the last 12 weeks&#xD;
&#xD;
         10. Individuals with a hypersensitivity to methotrexate or a recognised contraindication (&#xD;
             please see Methotrexate information sheet)&#xD;
&#xD;
         11. Individuals currently diagnosed with Type 1 reaction or Lucio's phenomenon&#xD;
&#xD;
         12. Individuals with the severe abnormalities in screening investigations&#xD;
&#xD;
         13. Positive serology for HIV, Hepatitis B or C&#xD;
&#xD;
         14. Evidence of tuberculosis or pulmonary fibrosis&#xD;
&#xD;
         15. A history of chronic liver disease or excessive alcohol or illicit substance&#xD;
             consumption&#xD;
&#xD;
         16. Individuals with severe inter-current infections, uncontrolled diabetes, active peptic&#xD;
             ulcer disease, untreated malignancy&#xD;
&#xD;
         17. Individuals unable to attend regularly for assessment or monitoring&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Stephen Walker, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>London School of Hygiene and Tropical Medicine</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Barbara de Barros, M.D</last_name>
    <phone>+44(0)2079272316</phone>
    <email>barbara.de-barros@lshtm.ac.uk</email>
  </overall_contact>
  <location>
    <facility>
      <name>TMLI Bangladesh/ DBLM hospital</name>
      <address>
        <city>Dhaka</city>
        <country>Bangladesh</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Benjamin Jewel Rozario</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>FIOCRUZ</name>
      <address>
        <city>Rio De Janeiro</city>
        <country>Brazil</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Jose' Nery</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>ALERT</name>
      <address>
        <city>Addis Ababa</city>
        <country>Ethiopia</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Saba Lambert</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>The Leprosy Mission Trust</name>
      <address>
        <city>Delhi</city>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Joydeepa Darlong</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Bombay Leprosy Project</name>
      <address>
        <city>Mumbai</city>
        <country>India</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vivek Pai</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Soetomo Hospital</name>
      <address>
        <city>Surabaya</city>
        <country>Indonesia</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Medhi Alinda</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Anandaban Hospital</name>
      <address>
        <city>Kathmandu</city>
        <country>Nepal</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Deanna Hagge</last_name>
    </contact>
  </location>
  <location_countries>
    <country>Bangladesh</country>
    <country>Brazil</country>
    <country>Ethiopia</country>
    <country>India</country>
    <country>Indonesia</country>
    <country>Nepal</country>
  </location_countries>
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    <citation>Li Y, Jiang L, Zhang S, Yin L, Ma L, He D, Shen J. Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. Rheumatol Int. 2012 Aug;32(8):2415-22. doi: 10.1007/s00296-011-1867-1. Epub 2011 Jun 21.</citation>
    <PMID>21691744</PMID>
  </reference>
  <reference>
    <citation>Reinhold-Keller E, de Groot K. Use of methotrexate in ANCA-associated vasculitides. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S178-82. Epub 2010 Oct 28.</citation>
    <PMID>21044456</PMID>
  </reference>
  <reference>
    <citation>Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013 Oct;45(2):202-10. doi: 10.1007/s12016-012-8351-x.</citation>
    <PMID>23334898</PMID>
  </reference>
  <reference>
    <citation>Davatchi F, Shams H, Shahram F, Nadji A, Chams-Davatchi C, Sadeghi Abdollahi B, Faezi T, Akhlaghi M, Ashofteh F. Methotrexate in ocular manifestations of Behcet's disease: a longitudinal study up to 15 years. Int J Rheum Dis. 2013 Oct;16(5):568-77. doi: 10.1111/1756-185X.12139. Epub 2013 Jul 4.</citation>
    <PMID>24164845</PMID>
  </reference>
  <reference>
    <citation>Warren RB, Griffiths CE. The potential of pharmacogenetics in optimizing the use of methotrexate for psoriasis. Br J Dermatol. 2005 Nov;153(5):869-73. doi: 10.1111/j.1365-2133.2005.06880.x.</citation>
    <PMID>16225593</PMID>
  </reference>
  <reference>
    <citation>Warren RB, Griffiths CE. Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin Dermatol. 2008 Sep-Oct;26(5):438-47. doi: 10.1016/j.clindermatol.2007.11.006.</citation>
    <PMID>18755362</PMID>
  </reference>
  <reference>
    <citation>Dalrymple JM, Stamp LK, O'Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008 Nov;58(11):3299-308. doi: 10.1002/art.24034.</citation>
    <PMID>18975321</PMID>
  </reference>
  <reference>
    <citation>Kaur I, Dogra S, Narang T, De D. Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol. 2009 Aug;50(3):181-5. doi: 10.1111/j.1440-0960.2009.00534.x. Erratum In: Australas J Dermatol. 2009 Nov;50(4):307.</citation>
    <PMID>19659979</PMID>
  </reference>
  <reference>
    <citation>Warren RB, Weatherhead SC, Smith CH, Exton LS, Mohd Mustapa MF, Kirby B, Yesudian PD. British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol. 2016 Jul;175(1):23-44. doi: 10.1111/bjd.14816. No abstract available. Erratum In: Br J Dermatol. 2017 Jun;176(6):1678.</citation>
    <PMID>27484275</PMID>
  </reference>
  <reference>
    <citation>World Health Organization. WHO Expert Committee on Leprosy. World Health Organ Tech Rep Ser. 2012;(968):1-61, 1 p following 61.</citation>
    <PMID>22970604</PMID>
  </reference>
  <reference>
    <citation>Warren RB, Mrowietz U, von Kiedrowski R, Niesmann J, Wilsmann-Theis D, Ghoreschi K, Zschocke I, Falk TM, Blodorn-Schlicht N, Reich K. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Feb 4;389(10068):528-537. doi: 10.1016/S0140-6736(16)32127-4. Epub 2016 Dec 22.</citation>
    <PMID>28012564</PMID>
  </reference>
  <reference>
    <citation>Reich K, Langley RG, Papp KA, Ortonne JP, Unnebrink K, Kaul M, Valdes JM. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med. 2011 Oct 27;365(17):1586-96. doi: 10.1056/NEJMoa1010858.</citation>
    <PMID>22029980</PMID>
  </reference>
  <verification_date>March 2023</verification_date>
  <study_first_submitted>November 29, 2018</study_first_submitted>
  <study_first_submitted_qc>December 13, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 14, 2018</study_first_posted>
  <last_update_submitted>March 10, 2023</last_update_submitted>
  <last_update_submitted_qc>March 10, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Erythema Nodosum Leprosum</keyword>
  <keyword>ENL</keyword>
  <keyword>corticosteroids</keyword>
  <keyword>Methotrexate</keyword>
  <keyword>ENL severity scale</keyword>
  <keyword>quality of life</keyword>
  <keyword>Leprosy</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Erythema</mesh_term>
    <mesh_term>Erythema Nodosum</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Methotrexate</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03775460
org study id: 15762
nct id: NCT03775460
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
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.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Proportion of individuals free from Erythema Nodosum Leprosum (ENL) flares in 24 weeks
time frame: During the first 24 weeks
description: 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.
measure: Proportion of individuals free from ENL flares in 48 weeks
time frame: During first 48 weeks
description: 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
measure: Change in ENLIST ENL severity scale score (EESS)
time frame: 60 weeks
description: 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
measure: Quality of life changes: 36- Item Short Form (SF-36) questionnaire
time frame: at 24 and 48 weeks
description: 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.
measure: Quality of life changes regarding skin condition: Dermatology life quality Index (DLQI)
time frame: at 24 and 48 weeks
description: 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.
measure: Proportion of individuals free from ENL flares at 60 weeks
time frame: 60 weeks
description: Proportion of individuals who do not require prednisolone at 60 weeks
measure: ENL flares per individual up to 60 weeks
time frame: 60 weeks
description: Number of flares of ENL per individual requiring additional prednisolone up to 60 weeks
measure: Severity of ENL flares
time frame: 60 weeks
description: 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
measure: Time to the first flare of ENL
time frame: 60 weeks
description: How long it takes to a participant who has an ENL flare to present with first episode of flare after enrolment
measure: Adverse effects
time frame: 60 weeks
description: Proportion of individuals with treatment related adverse effects
measure: Quality of life at 60 weeks: SF-36 questionnaire
time frame: 60 weeks
description: 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
measure: Quality of life at 60 weeks regarding skin condition: Dermatology Life Quality Index (DLQI) questionnaires
time frame: 60 weeks
description: 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.
measure: Individuals free from ENL flares in 60 weeks
time frame: 60 weeks
description: Proportion of individuals who have not required additional prednisolone in the 60 weeks of the trial
arm group label: control
arm group type: Placebo Comparator
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.
arm group label: intervention
arm group type: Experimental
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.
intervention type: Drug
intervention name: Methotrexate
description: Participants in the intervention group will receive methotrexate along side prednisolone
arm group label: intervention
intervention type: Drug
intervention name: Placebo
description: Participants in the control arm will receive placebo along side prednisolone
arm group label: control
intervention type: Drug
intervention name: Prednisolone
description: Participants in both arm will receive prednisolone, which will be the same dosage: 40 mg (initial dose) decreasing dosage for 20 weeks
arm group label: control
arm group label: intervention
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
last name: Stephen Walker, MD, PhD
role: Principal Investigator
affiliation: London School of Hygiene and Tropical Medicine
last name: Barbara de Barros, M.D
phone: +44(0)2079272316
email: barbara.de-barros@lshtm.ac.uk
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
country: Bangladesh
country: Brazil
country: Ethiopia
country: India
country: Indonesia
country: Nepal
citation: Lambert SM, Nigusse SD, Alembo DT, Walker SL, Nicholls PG, Idriss MH, Yamuah LK, Lockwood DN. Comparison of Efficacy and Safety of Ciclosporin to Prednisolone in the Treatment of Erythema Nodosum Leprosum: Two Randomised, Double Blind, Controlled Pilot Studies in Ethiopia. PLoS Negl Trop Dis. 2016 Feb 26;10(2):e0004149. doi: 10.1371/journal.pntd.0004149. eCollection 2016 Feb.
PMID: 26919207
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PMID: 16687695
citation: Kumar B, Dogra S, Kaur I. Epidemiological characteristics of leprosy reactions: 15 years experience from north India. Int J Lepr Other Mycobact Dis. 2004 Jun;72(2):125-33. doi: 10.1489/1544-581X(2004)0722.0.CO;2.
PMID: 15301592
citation: Chandler DJ, Hansen KS, Mahato B, Darlong J, John A, Lockwood DN. Household costs of leprosy reactions (ENL) in rural India. PLoS Negl Trop Dis. 2015 Jan 15;9(1):e0003431. doi: 10.1371/journal.pntd.0003431. eCollection 2015 Jan.
PMID: 25590638
citation: Walker SL, Lebas E, Doni SN, Lockwood DN, Lambert SM. The mortality associated with erythema nodosum leprosum in Ethiopia: a retrospective hospital-based study. PLoS Negl Trop Dis. 2014 Mar 13;8(3):e2690. doi: 10.1371/journal.pntd.0002690. eCollection 2014 Mar.
PMID: 24625394
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citation: Polycarpou A, Walker SL, Lockwood DN. A Systematic Review of Immunological Studies of Erythema Nodosum Leprosum. Front Immunol. 2017 Mar 13;8:233. doi: 10.3389/fimmu.2017.00233. eCollection 2017.
PMID: 28348555
citation: Hossain D. Using methotrexate to treat patients with ENL unresponsive to steroids and clofazimine: a report on 9 patients. Lepr Rev. 2013 Mar;84(1):105-12.
PMID: 23741889
citation: Kar BR, Babu R. Methotrexate in resistant ENL. Int J Lepr Other Mycobact Dis. 2004 Dec;72(4):480-2. doi: 10.1489/1544-581X(2004)722.0.CO;2.
PMID: 15755203
citation: Rahul N, Sanjay KS, Singh S. Effectiveness of Methotrexate in prednisolone and thalidomide resistant cases of Type 2 lepra reaction: report on three cases. Lepr Rev. 2015 Dec;86(4):379-82. No abstract available.
PMID: 26964434
citation: Sousa AL, Fava VM, Sampaio LH, Martelli CM, Costa MB, Mira MT, Stefani MM. Genetic and immunological evidence implicates interleukin 6 as a susceptibility gene for leprosy type 2 reaction. J Infect Dis. 2012 May 1;205(9):1417-24. doi: 10.1093/infdis/jis208. Epub 2012 Mar 29.
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citation: Rajappa M, Rathika S, Munisamy M, Chandrashekar L, Thappa DM. Effect of treatment with methotrexate and coal tar on adipokine levels and indices of insulin resistance and sensitivity in patients with psoriasis vulgaris. J Eur Acad Dermatol Venereol. 2015 Jan;29(1):69-76. doi: 10.1111/jdv.12451. Epub 2014 Mar 25.
PMID: 24665910
citation: Martiniuk F, Giovinazzo J, Tan AU, Shahidullah R, Haslett P, Kaplan G, Levis WR. Lessons of leprosy: the emergence of TH17 cytokines during type II reactions (ENL) is teaching us about T-cell plasticity. J Drugs Dermatol. 2012 May;11(5):626-30.
PMID: 22527432
citation: Li Y, Jiang L, Zhang S, Yin L, Ma L, He D, Shen J. Methotrexate attenuates the Th17/IL-17 levels in peripheral blood mononuclear cells from healthy individuals and RA patients. Rheumatol Int. 2012 Aug;32(8):2415-22. doi: 10.1007/s00296-011-1867-1. Epub 2011 Jun 21.
PMID: 21691744
citation: Reinhold-Keller E, de Groot K. Use of methotrexate in ANCA-associated vasculitides. Clin Exp Rheumatol. 2010 Sep-Oct;28(5 Suppl 61):S178-82. Epub 2010 Oct 28.
PMID: 21044456
citation: Marzano AV, Ishak RS, Saibeni S, Crosti C, Meroni PL, Cugno M. Autoinflammatory skin disorders in inflammatory bowel diseases, pyoderma gangrenosum and Sweet's syndrome: a comprehensive review and disease classification criteria. Clin Rev Allergy Immunol. 2013 Oct;45(2):202-10. doi: 10.1007/s12016-012-8351-x.
PMID: 23334898
citation: Davatchi F, Shams H, Shahram F, Nadji A, Chams-Davatchi C, Sadeghi Abdollahi B, Faezi T, Akhlaghi M, Ashofteh F. Methotrexate in ocular manifestations of Behcet's disease: a longitudinal study up to 15 years. Int J Rheum Dis. 2013 Oct;16(5):568-77. doi: 10.1111/1756-185X.12139. Epub 2013 Jul 4.
PMID: 24164845
citation: Warren RB, Griffiths CE. The potential of pharmacogenetics in optimizing the use of methotrexate for psoriasis. Br J Dermatol. 2005 Nov;153(5):869-73. doi: 10.1111/j.1365-2133.2005.06880.x.
PMID: 16225593
citation: Warren RB, Griffiths CE. Systemic therapies for psoriasis: methotrexate, retinoids, and cyclosporine. Clin Dermatol. 2008 Sep-Oct;26(5):438-47. doi: 10.1016/j.clindermatol.2007.11.006.
PMID: 18755362
citation: Dalrymple JM, Stamp LK, O'Donnell JL, Chapman PT, Zhang M, Barclay ML. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2008 Nov;58(11):3299-308. doi: 10.1002/art.24034.
PMID: 18975321
citation: Kaur I, Dogra S, Narang T, De D. Comparative efficacy of thalidomide and prednisolone in the treatment of moderate to severe erythema nodosum leprosum: a randomized study. Australas J Dermatol. 2009 Aug;50(3):181-5. doi: 10.1111/j.1440-0960.2009.00534.x. Erratum In: Australas J Dermatol. 2009 Nov;50(4):307.
PMID: 19659979
citation: Warren RB, Weatherhead SC, Smith CH, Exton LS, Mohd Mustapa MF, Kirby B, Yesudian PD. British Association of Dermatologists' guidelines for the safe and effective prescribing of methotrexate for skin disease 2016. Br J Dermatol. 2016 Jul;175(1):23-44. doi: 10.1111/bjd.14816. No abstract available. Erratum In: Br J Dermatol. 2017 Jun;176(6):1678.
PMID: 27484275
citation: World Health Organization. WHO Expert Committee on Leprosy. World Health Organ Tech Rep Ser. 2012;(968):1-61, 1 p following 61.
PMID: 22970604
citation: Warren RB, Mrowietz U, von Kiedrowski R, Niesmann J, Wilsmann-Theis D, Ghoreschi K, Zschocke I, Falk TM, Blodorn-Schlicht N, Reich K. An intensified dosing schedule of subcutaneous methotrexate in patients with moderate to severe plaque-type psoriasis (METOP): a 52 week, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017 Feb 4;389(10068):528-537. doi: 10.1016/S0140-6736(16)32127-4. Epub 2016 Dec 22.
PMID: 28012564
citation: Reich K, Langley RG, Papp KA, Ortonne JP, Unnebrink K, Kaul M, Valdes JM. A 52-week trial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med. 2011 Oct 27;365(17):1586-96. doi: 10.1056/NEJMoa1010858.
PMID: 22029980
responsible party type: Sponsor
mesh term: Erythema
mesh term: Erythema Nodosum
mesh term: Prednisolone
mesh term: Methotrexate
sharing ipd: No