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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 : November 7, 2017
Sponsor:
Collaborator:
Cristália Produtos Químicos Farmacêuticos Ltda.
Information provided by (Responsible Party):
Daniel Ciampi Araujo de Andrade, MD, PhD, University of Sao Paulo

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

Condition or disease Intervention/treatment Phase
Pain, Neuropathic Leprosy Leprosy Neuropathy Amitriptyline Drug: Amitriptyline Drug: Placebo oral capsule Drug: Tramadol Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Treatment of Neuropathic Pain in Leprosy: a Randomized Double Blind Controlled Study
Actual Study Start Date : March 1, 2017
Estimated Primary Completion Date : March 2019
Estimated Study Completion Date : March 2019

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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: Tramadol
Administer to both arms on "as needed" scheme, to a maximum of 150mg/day.

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.
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.




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. Neuropathic pain [ Time Frame: 63 days (9 weeks) ]
    DN4 (douleur neuropathique 4) + (≥ 4/10)

  2. 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)

  3. 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).

  4. 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

  5. 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)

  6. 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

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): NCT03324035


Contacts
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Contact: Renato Pazzini, MD 5511974429181 renatopazzini@me.com
Contact: Daniel Andrade, PhD 5511997753538 ciampi@usp.br

Locations
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Brazil
Hospital Das Clínicas da Faculdade de Medicina da USP Recruiting
São Paulo, SP, Brazil, 05403-010
Contact: Renato Pazzini, MD    5511974429181    renatopazzini@me.com   
Contact: Daniel AC Andrade, PhD    5511997753538    ciampi@usp.br   
Sub-Investigator: Maria AB Trindade, PhD         
Sub-Investigator: Gil Bernard, PhD         
Sub-Investigator: Antonia LL Rodrigues         
Sub-Investigator: Ricardo Galhardoni, PhD         
Sub-Investigator: Manoel J Teixeira, PhD         
Sub-Investigator: Wagner Galvão, MD         
Sub-Investigator: Renato Pazzini, MD         
Principal Investigator: Daniel AC Andrade, PhD         
Sub-Investigator: Valquiria A Silva         
Sponsors and Collaborators
University of Sao Paulo
Cristália Produtos Químicos Farmacêuticos Ltda.
Investigators
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Principal Investigator: Daniel Andrade, PhD University of Sao Paulo

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Responsible Party: Daniel Ciampi Araujo de Andrade, MD, PhD, Principal Investigator, Pain Center coordinator, Department of Neurology, University of Sao Paulo, São Paulo, Brazil, University of Sao Paulo
ClinicalTrials.gov Identifier: NCT03324035     History of Changes
Other Study ID Numbers: AmyNeLe
First Posted: October 27, 2017    Key Record Dates
Last Update Posted: November 7, 2017
Last Verified: November 2017
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
Additional relevant MeSH terms:
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Leprosy
Neuralgia
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Pain
Neurologic Manifestations
Signs and Symptoms
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Tramadol
Amitriptyline
Amitriptyline, perphenazine drug combination
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Antidepressive Agents, Tricyclic
Antidepressive Agents
Psychotropic Drugs
Analgesics, Non-Narcotic
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action