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Treatment of Neuropathic Pain in Leprosy (AmyNeLe)

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ClinicalTrials.gov Identifier: NCT03324035
Recruitment Status : Recruiting
First Posted : October 27, 2017
Last Update Posted : December 28, 2020
Sponsor:
Collaborator:
Cristália Produtos Químicos Farmacêuticos Ltda.
Information provided by (Responsible Party):
Daniel Ciampi Araujo de Andrade, MD, PhD, University of Sao Paulo

Tracking Information
First Submitted Date  ICMJE June 14, 2017
First Posted Date  ICMJE October 27, 2017
Last Update Posted Date December 28, 2020
Actual Study Start Date  ICMJE March 1, 2017
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 4, 2017)
Reduction in pain intensity of 30% from baseline measured by verbal analog scale (VAS) [ Time Frame: 63 days (9 weeks) ]
To evaluate the analgesic effect of amitriptyline in flexible dose in patients with neuropathic pain associated with leprosy compared to placebo on the Visual Analogic Scale (VAS) (range 100mm- minimum 0 and maximum 100)
Original Primary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
Reduction in pain intensity of 30% from baseline [ Time Frame: 63 days (9 weeks) ]
To evaluate the analgesic effect of amitriptyline in flexible dose in patients with neuropathic pain associated with leprosy compared to placebo on the Visual Analogic Scale (VAS)
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2017)
  • Neuropathic pain [ Time Frame: 63 days (9 weeks) ]
    DN4 (douleur neuropathique 4) + (≥ 4/10)
  • Neuropathic Pain Symptoms [ Time Frame: 63 days (9 weeks) ]
    To assess the effectiveness of amitriptyline on the reduction of painful symptoms, and on neuropathic dimensions evaluated by the NPSI questionnaire (minimum 0 and maximum 100)
  • Quality of Life [ Time Frame: 63 days (9 weeks) ]
    To assess the impact of amitriptyline on the patient's quality of life, depressive and anxiety symptoms, quality of sleep, through the WHOQOL questionnaire (range 0 to 100).
  • Number of participants with treatment-related adverse events [ Time Frame: 63 days (9 weeks) ]
    To evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v4.03 score 0/1 vs 2/3/4
  • Predictive factor of response [ Time Frame: 63 days (9 weeks) ]
    assess whether pain phenotype A (NPSI baseline score <15) responded differently to the active drug compared to phenotype B (NPSI score at baseline ≥ 15)
  • Use of backup pain medication [ Time Frame: 63 days (9 weeks) ]
    To assess the difference in dosage of rescue medication (tramadol) between both treatment arms, by counting the number of pills of tramadol used by each patient.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 23, 2017)
  • Neuropathic pain [ Time Frame: 63 days (9 weeks) ]
    DN4 (douleur neuropathique 4) + (≥ 4/10)
  • NPSI [ Time Frame: 63 days (9 weeks) ]
    To assess the effectiveness of amitriptyline on the reduction of painful symptoms, and on neuropathic dimensions evaluated by the NPSI questionnaire
  • Quality of Life [ Time Frame: 63 days (9 weeks) ]
    To assess the impact of amitriptyline on the patient's quality of life, depressive and anxiety symptoms, quality of sleep, through the WHOQOL questionnaire
  • Number of participants with treatment-related adverse events [ Time Frame: 63 days (9 weeks) ]
    To evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v4.03 score 0/1 vs 2/3/4
  • Predictive factor of response [ Time Frame: 63 days (9 weeks) ]
    assess whether pain phenotype A (NPSI baseline score <15) responded differently to the active drug compared to phenotype B (NPSI score at baseline ≥ 15)
  • Use of backup pain medication [ Time Frame: 63 days (9 weeks) ]
    To assess the difference in dosage of rescue medication (tramadol) between both treatment arms, by counting the number of pills of tramadol used by each patient.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Treatment of Neuropathic Pain in Leprosy
Official Title  ICMJE Treatment of Neuropathic Pain in Leprosy: a Randomized Double Blind Controlled Study
Brief Summary Despite large efforts to eradicate leprosy, this curable mycobacterial infection still affects 250,000 new individuals annually. Half of the globe's leprosy patients live in Brazil and India. In 2013, 33,033 new leprosy cases diagnosed in Brazil, with an average incidence of 1.05 cases / 10 000 inhabitants. Recently a new concept of care after cure has called attention for severe pain in previously treated patients, particularly, neuropathic pain. Even so, until now no single drug has been studied for the treatment of pain in this patients, and the use of drugs is based on the study of other diseases. We designed the first placebo-controlled, double blinded randomized trial in the use of flexible-dose amitriptyline (tricyclic antidepressant) for the treatment of neuropathic pain related to leprosy
Detailed Description

Despite large efforts to eradicate leprosy, this curable mycobacterial infection still affects 250,000 new individuals annually. Half of the globe's leprosy patients live in Brazil and India. In 2013, 33,033 new leprosy cases diagnosed in Brazil, with an average incidence of 1.05 cases / 10 000 inhabitants. Most new cases occur in economically restricted regions of the world, but because at least 5% of the general population is genetically susceptible to the causative agent, new cases may occur anywhere worldwide. This is especially true in times of high human geographic dislocation. Thus, leprosy should rank among the differential diagnosis list of general practitioners and specialists treating skin and peripheral nerve disorders even in non-endemic areas.

Mycobacterium leprae is an obligatory intracellular bacterium that invades macrophages and Schwann cells. Although myelinating Schwann cells are relatively resistant to invasion, viable M. leprae cause marked myelin destruction and lead to secondary neuronal phenotypic changes, degeneration, and nerve dysfunction.

Leprosy patients have historically been characterized by cutaneous insensibility in body areas of deformity, and the presence of pain in these patients has been neglected for a long time. It has only been recently acknowledged that leprosy can be associated with pain in general and neuropathic pain in particular. Leprosy patients frequently experience neuropathy in wide areas of the body, which may or may not present with pain. When pain exists, it may be acute or chronic, neuropathic or inflammatory. Leprosy has different clinical presentations (according to the host's innate immune response) that range from localized skin lesions and adjacent intra-epidermal nerve fiber injury to widespread neuropathy distributed in large areas of low body-surface temperature. Neuropathic pain in leprosy may affect 11-22% of patients, and up to 56% of those with chronic pain. Importantly, more than 85% of patients with leprosy-related neuropathic pain developed it after the end of the antimicrobial treatment period. This means that the majority of patients who developed neuropathic pain did so after they were formally cured of the disease, and, in many cases, discharged from medical assistance. Therefore, pain in leprosy can also be inserted as part of the "care after cure" program initiative, along with stigma, deformity and incapacity management strategies.

In recent years several easy-to use screening tools have been developed to screen for neuropathic pain in leprosy patients, such as the douleur neuropathique-4 (DN-4) and others. These tools allow for the rapid (usually 20 seconds to administer) and reliable (high sensitivity) assessment of pain in leprosy patients.

Additionally, very few reports have described he effects of treatment used for neuropathic pain in these patients, and no clinical trials have been conducted for this specific condition to date. One could argue that leprosy patients with neuropathic pain should respond to usual drugs such as tricyclic antidepressants and anticonvulsants (and they usually do), but the selection of the appropriate treatment regimen, the proper timing of treatment initiation and the most cost-effective drug is not an obvious task. Also, and very important, the lack of formal evidence-based data attesting the efficacy of tricyclics and anticonvulsants for the treatment of leprosy associated neuropathic pain hampers further a wider availability of these drugs in economically-restricted areas. All these limitations can be overcome if the current scientific interest in pain in leprosy is maintained and the present high-level research in the area continues to grow similarly to the previous decades.

Here we designed the first placebo-controlled, double blinded randomized trial in the use of flexible-dose amitriptyline (tricyclic antidepressant) for the treatment of neuropathic pain related to leprosy. This study is currently approved by our local Ethics Review Board (CAAE: 45393415.9.0000.0068) and has stared the recruitment phase on March 2017.

Recruitment time will be extended by 12 months due to dropouts related to the Covid pandemic. We have had dropouts due to a few patients developing covid and also due to patients having fear to become infected while attending hospital visits."

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Pain, Neuropathic
  • Leprosy
  • Leprosy Neuropathy
  • Amitriptyline
Intervention  ICMJE
  • Drug: Amitriptyline
    Administer amitriptyline on flexible doses variating from 25mg to 75mg, with backup of tramadol, and evaluate the reduction of the pain based on the Brief Pain Inventory Questionnaire.
  • Drug: Placebo oral capsule
    Administer amitriptyline on flexible doses variating from 1 to 3 capsules, with backup of tramadol, and evaluate the reduction of the pain based on the Brief Pain Inventory Questionnaire.
  • Drug: Tramadol
    Administer to both arms on "as needed" scheme, to a maximum of 150mg/day.
Study Arms  ICMJE
  • Experimental: Treatment
    Patients on this arm will receive amitriptyline on flexible doses, starting from 25mg (1 capsule) and titrated to 50mg (2 capsules) or 75mg (3 capsules), based on brief pain inventory (BPI) questionnaire, applied weekly for 3 consecutive weeks. All patients will receive tramadol as a supportive drug for the treatment of neuropathic pain, they are instructed to take 50mg every 8 hours, if pain present.
    Interventions:
    • Drug: Amitriptyline
    • Drug: Tramadol
  • Placebo Comparator: Placebo
    Patients on this arm will receive placebo on flexible doses, starting from 1 capsule and titrated to 2 capsules or 3 capsules, based on brief pain inventory (BPI) questionnaire, applied weekly for 3 consecutive weeks. All patients will receive tramadol as a supportive drug for the treatment of neuropathic pain, they are instructed to take 50mg every 8 hours, if pain present.
    Interventions:
    • Drug: Placebo oral capsule
    • Drug: Tramadol
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 23, 2017)
102
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Presence of spontaneous pain of medium intensity in the last 24 hours with a minimum value of 4 in 10 on a numerical scale, with a maximum of 10 points (summed pain questionnaire)
  • Duration of pain of at least 6 months
  • Presence of neuropathic pain "pure" or of clearly dominant character (no other pain, or pain associated unimportant)
  • Pain due to leprosy confirmed by clinical examination and / or appropriate electrophysiological examination
  • Ability to properly understand the Portuguese language, being able to understand the methodology of the study and questionnaires
  • Having provided their consent in writing of their participation in the study

Exclusion Criteria:

  • Linked to the disease in study:
  • Neuropathic pain from other causes that not Hansen's disease (Diabetes, HIV, and after chemotherapy);
  • Linked to the treatment:
  • Hypersensitivity to amitriptyline and tramadol;
  • Ongoing treatment with monoamine oxidase inhibitors (MAOIs);
  • Cardiac and ophthalmologic disorders that contraindicate the use of amitryptiline;
  • Pregnant or nursing women, or even women of childbearing age without the use of contraceptives.
  • General
  • Other pain with intensity higher then the neuropathic one;
  • Ant other condition that may interfere with the evaluation of the study;
  • Patients who have not given or signed the informed consent form;
  • Incorrectly completion of the self-assessment of pain notebook in the period between inclusion and randomization (at least 4 scores in 7 days);
  • Patients who can't be followed on a regular basis or that miss the appointments (we will give a 7 day tolerance for each appointment);
  • Documented abuse of psychoactive drugs or alcohol;
  • History of past or actual psychosis;
  • Actual diagnosis of major depression following the DSM-IV criteria;
  • Language and cognitive deficits that are capable of interfering with the understanding of the study;
  • Patients not affiliated with a social security scheme (beneficiary or recipient);
  • Patients who refuses to sign or are unable to understand the informed consent, under guardianship;
  • Participation in other research protocol involving the use of any medication during the 30 days preceding the inclusion in the project.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Renato Pazzini, MD 5511974429181 renatopazzini@me.com
Contact: Daniel Andrade, PhD 5511997753538 ciampi@usp.br
Listed Location Countries  ICMJE Brazil
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03324035
Other Study ID Numbers  ICMJE AmyNeLe
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Daniel Ciampi Araujo de Andrade, MD, PhD, University of Sao Paulo
Study Sponsor  ICMJE University of Sao Paulo
Collaborators  ICMJE Cristália Produtos Químicos Farmacêuticos Ltda.
Investigators  ICMJE
Principal Investigator: Daniel Andrade, PhD University of Sao Paulo
PRS Account University of Sao Paulo
Verification Date December 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP