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Treatment of Neuropathic Pain in Leprosy (AmyNeLe)

Primary Purpose

Pain, Neuropathic, Leprosy, Leprosy Neuropathy

Status
Active
Phase
Phase 3
Locations
Brazil
Study Type
Interventional
Intervention
Amitriptyline
Placebo oral capsule
Tramadol
Sponsored by
University of Sao Paulo
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Pain, Neuropathic

Eligibility Criteria

18 Years - 85 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Hospital Das Clínicas da Faculdade de Medicina da USP

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Treatment

Placebo

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Reduction in pain intensity of 30% from baseline measured by verbal analog scale (VAS)
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)

Secondary Outcome Measures

Neuropathic pain
DN4 (douleur neuropathique 4) + (≥ 4/10)
Neuropathic Pain Symptoms
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)
Mensure Quality of Life
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
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
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
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.

Full Information

First Posted
June 14, 2017
Last Updated
February 4, 2022
Sponsor
University of Sao Paulo
Collaborators
Cristália Produtos Químicos Farmacêuticos Ltda.
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1. Study Identification

Unique Protocol Identification Number
NCT03324035
Brief Title
Treatment of Neuropathic Pain in Leprosy
Acronym
AmyNeLe
Official Title
Treatment of Neuropathic Pain in Leprosy: a Randomized Double Blind Controlled Study
Study Type
Interventional

2. Study Status

Record Verification Date
February 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 1, 2017 (Actual)
Primary Completion Date
May 3, 2021 (Actual)
Study Completion Date
August 1, 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Sao Paulo
Collaborators
Cristália Produtos Químicos Farmacêuticos Ltda.

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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."

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Pain, Neuropathic, Leprosy, Leprosy Neuropathy, Amitriptyline

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
102 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Treatment
Arm Type
Experimental
Arm Description
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.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Amitriptyline
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Placebo oral capsule
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Tramadol
Intervention Description
Administer to both arms on "as needed" scheme, to a maximum of 150mg/day.
Primary Outcome Measure Information:
Title
Reduction in pain intensity of 30% from baseline measured by verbal analog scale (VAS)
Description
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)
Time Frame
63 days (9 weeks)
Secondary Outcome Measure Information:
Title
Neuropathic pain
Description
DN4 (douleur neuropathique 4) + (≥ 4/10)
Time Frame
63 days (9 weeks)
Title
Neuropathic Pain Symptoms
Description
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)
Time Frame
63 days (9 weeks)
Title
Mensure Quality of Life
Description
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).
Time Frame
63 days (9 weeks)
Title
Number of participants with treatment-related adverse events
Description
To evaluate the number of participants with treatment-related adverse events as assessed by CTCAE v4.03 score 0/1 vs 2/3/4
Time Frame
63 days (9 weeks)
Title
Predictive factor of response
Description
assess whether pain phenotype A (NPSI baseline score <15) responded differently to the active drug compared to phenotype B (NPSI score at baseline ≥ 15)
Time Frame
63 days (9 weeks)
Title
Use of backup pain medication
Description
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.
Time Frame
63 days (9 weeks)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
85 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Daniel Andrade, PhD
Organizational Affiliation
University of Sao Paulo
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Das Clínicas da Faculdade de Medicina da USP
City
São Paulo
State/Province
SP
ZIP/Postal Code
05403-010
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
No

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Treatment of Neuropathic Pain in Leprosy

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