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Efficacy and Safety Study of Drugs for Treatment of Visceral Leishmaniasis in Brazil (LVBrasil)

Primary Purpose

Visceral Leishmaniasis

Status
Terminated
Phase
Phase 4
Locations
Brazil
Study Type
Interventional
Intervention
Antimoniate of N-methylglucamine
amphotericin B deoxycholate
Liposomal amphotericin B
Liposomal amphotericin B
Antimoniate of N-methylglucamine
Sponsored by
University of Brasilia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Visceral Leishmaniasis focused on measuring Visceral leishmaniasis, Leishmania infantum, Leishmania chagasi

Eligibility Criteria

6 Months - 50 Years (Child, Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • patients with visceral leishmaniasis characterized by fever plus hepatomegaly or splenomegaly with at least one positive result in the following laboratory tests:
  • direct observation of leishmania amastigotes in bone marrow smear
  • leishmania in vitro culture from bone marrow aspirates
  • leishmania kDNA amplification by PCR in bone marrow or peripheral blood samples
  • rK39 immunochromatographic rapid test performed on serum sample

Exclusion Criteria:

  • pregnancy
  • HIV infection
  • chronic diseases such as diabetes mellitus,kidney, liver or cardiac diseases, schistosomiasis, malaria or tuberculosis
  • immune disorders or use of drugs which interferes with the immune response
  • treatment with drugs with increased risk for toxicity associated with the study drugs
  • exposure to antileishmanial drugs during the past six months
  • I.V. drug users
  • episodes of visceral leishmaniasis relapse
  • hypersensibility to the study drugs
  • difficulties for accomplishing the follow-up schedule
  • any of the following clinical signs of laboratory abnormalities: hepatic encephalopathy, generalized edema, toxemic individuals, severe malnutrition, jaundice, abnormal serum creatinine, bilirubin, INR > 2,0, platelet count < 20000/mm3

Sites / Locations

  • Hospital Universitário da Universidade Federal de Sergipe
  • Hospital São José de Doenças Infecciosas
  • Hospital Infantil João Paulo II - FHEMIG
  • Hospital Universitário Clemente de Faria - Universidade Estadual de Montes Claros
  • Hospital de Doencas Infecto Contagiosas - HDIC

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Experimental

Experimental

Arm Label

Meglumine antimoniate

Liposomal Amphotericin B

Amphotericin B

Combination therapy

Arm Description

Antimoniate of N-methylglucamine 20mg/kg/d, I.V. for 20 consecutive days.

Liposomal amphotericin B 3mg/kg/d I.V. for 7 consecutive days.

Amphotericin B deoxycholate 1mg/kg/d I.V. for 14 consecutive days. This arm was suspended in September 19th, 2012, because of a relevant excess of adverse events and serious adverse events associated with this experimental intervention in comparison with the active comparator and the other two experimental arms. The suspension of this study arm was supported by a DSMB statement.

Liposomal amphotericin B 10mg/kg/d, I.V. single dose on day 0 plus Antimoniate of N-methylglucamine 20mg/kg/d for 10 consecutive days on days 1 to 10.

Outcomes

Primary Outcome Measures

Cure rate
Complete remission of clinical signs and symptoms, three months after treatment plus normal hematological lab evaluation and no relapse at sixth month follow-up.

Secondary Outcome Measures

Improvement rate
Fever disappearing, stable or improving hematological lab abnormalities plus any spleen size reduction.
Relapse rate
Reappearing of signs and symptoms after any improvement observed after treatment, during the six months follow-up period.
Serious adverse events rate
Rate of adverse events defined as conditions which fulfilled any of the following: results in death, is life threatening, requires inpatient hospitalization or prolongs hospitalization, results in persistent or significant disability/incapacity, causes a congenital anomaly or birth defect or it is considered as a important medical event for the responsible clinician.
Adverse event rate and intensity
Cumulative rate of any adverse event, including clinical, laboratory and electrocardiographic abnormalities observed within the treatment and follow-up periods. All adverse events will be graded using an adapted ACTG 0-4 scale.

Full Information

First Posted
March 7, 2011
Last Updated
August 31, 2017
Sponsor
University of Brasilia
Collaborators
Ministry of Health, Brazil, Drugs for Neglected Diseases, Conselho Nacional de Desenvolvimento Científico e Tecnológico
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1. Study Identification

Unique Protocol Identification Number
NCT01310738
Brief Title
Efficacy and Safety Study of Drugs for Treatment of Visceral Leishmaniasis in Brazil
Acronym
LVBrasil
Official Title
Multicentric Efficacy and Safety Study of Antileishmanial Drugs for Treatment of Visceral Leishmaniasis in Brazil
Study Type
Interventional

2. Study Status

Record Verification Date
August 2017
Overall Recruitment Status
Terminated
Why Stopped
DSMB recommendation based on programmed interim analysis.
Study Start Date
February 2011 (undefined)
Primary Completion Date
October 2014 (Actual)
Study Completion Date
February 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Brasilia
Collaborators
Ministry of Health, Brazil, Drugs for Neglected Diseases, Conselho Nacional de Desenvolvimento Científico e Tecnológico

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This study is aimed to compare the efficacy and safety of medications currently used in Brazil for treatment of visceral leishmaniasis. The investigators will compare the effects of meglumine antimoniate, two formulations of amphotericin B: deoxycholate and liposomal, and a combination of meglumine plus the liposomal amphotericin B formulation. The study is designed to demonstrate the difference in efficacy measured as cure rate at six months after treatment and the safety profile based on the adverse event rate observed with each intervention.
Detailed Description
Visceral leishmaniasis is a relevant public health problem in Brazil with approximately 3500 cases registered every year. Eight percent lethality rate has been observed during the past decade in spite of free of charge availability of antileishmanial drugs supplied by the public health system. The present study was designed as a phase IV, multicentric, open label, active controlled clinical trial targeted to visceral leishmaniasis adult and pediatric cases. The current drugs approved for visceral leishmaniasis treatment in Brazil will be compared in four treatment groups: meglumine antimoniate, amphotericin B deoxycholate, liposomal amphotericin B and a combination of single dose of liposomal amphotericin B plus meglumine antimoniate. Meglumine antimoniate treated patients will constitute the active control group. Drugs will be compared based on the cure rate observed after six months follow-up. The study arm submitted to treatment with Amphotericin B deoxycholate was suspended in September 2012.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Visceral Leishmaniasis
Keywords
Visceral leishmaniasis, Leishmania infantum, Leishmania chagasi

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
378 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Meglumine antimoniate
Arm Type
Active Comparator
Arm Description
Antimoniate of N-methylglucamine 20mg/kg/d, I.V. for 20 consecutive days.
Arm Title
Liposomal Amphotericin B
Arm Type
Experimental
Arm Description
Liposomal amphotericin B 3mg/kg/d I.V. for 7 consecutive days.
Arm Title
Amphotericin B
Arm Type
Experimental
Arm Description
Amphotericin B deoxycholate 1mg/kg/d I.V. for 14 consecutive days. This arm was suspended in September 19th, 2012, because of a relevant excess of adverse events and serious adverse events associated with this experimental intervention in comparison with the active comparator and the other two experimental arms. The suspension of this study arm was supported by a DSMB statement.
Arm Title
Combination therapy
Arm Type
Experimental
Arm Description
Liposomal amphotericin B 10mg/kg/d, I.V. single dose on day 0 plus Antimoniate of N-methylglucamine 20mg/kg/d for 10 consecutive days on days 1 to 10.
Intervention Type
Drug
Intervention Name(s)
Antimoniate of N-methylglucamine
Other Intervention Name(s)
Glucantime
Intervention Description
Antimoniate of N-methyl glucamine 20mg/kg/d of pentavalent antimonial, I.V. for 20 consecutive days.
Intervention Type
Drug
Intervention Name(s)
amphotericin B deoxycholate
Other Intervention Name(s)
Fungizone, Anforicin B
Intervention Description
1mg/kg/d, I.V. for 14 consecutive days.
Intervention Type
Drug
Intervention Name(s)
Liposomal amphotericin B
Other Intervention Name(s)
AmBisome
Intervention Description
3mg/kg/d, I.V. for 7 consecutive days.
Intervention Type
Drug
Intervention Name(s)
Liposomal amphotericin B
Other Intervention Name(s)
AmBisome
Intervention Description
10mg/kg/d, I.V. single dose.
Intervention Type
Drug
Intervention Name(s)
Antimoniate of N-methylglucamine
Other Intervention Name(s)
Glucantime
Intervention Description
20mg/kg/d of pentavalent antimonial I.V. for 10 days
Primary Outcome Measure Information:
Title
Cure rate
Description
Complete remission of clinical signs and symptoms, three months after treatment plus normal hematological lab evaluation and no relapse at sixth month follow-up.
Time Frame
6 month
Secondary Outcome Measure Information:
Title
Improvement rate
Description
Fever disappearing, stable or improving hematological lab abnormalities plus any spleen size reduction.
Time Frame
30 days
Title
Relapse rate
Description
Reappearing of signs and symptoms after any improvement observed after treatment, during the six months follow-up period.
Time Frame
(6 months post treatment) After treatment until the sixth month of follow-up
Title
Serious adverse events rate
Description
Rate of adverse events defined as conditions which fulfilled any of the following: results in death, is life threatening, requires inpatient hospitalization or prolongs hospitalization, results in persistent or significant disability/incapacity, causes a congenital anomaly or birth defect or it is considered as a important medical event for the responsible clinician.
Time Frame
During (day one) and within the six months follow-up
Title
Adverse event rate and intensity
Description
Cumulative rate of any adverse event, including clinical, laboratory and electrocardiographic abnormalities observed within the treatment and follow-up periods. All adverse events will be graded using an adapted ACTG 0-4 scale.
Time Frame
During (day one) treatment and within the six months follow-up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Months
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: patients with visceral leishmaniasis characterized by fever plus hepatomegaly or splenomegaly with at least one positive result in the following laboratory tests: direct observation of leishmania amastigotes in bone marrow smear leishmania in vitro culture from bone marrow aspirates leishmania kDNA amplification by PCR in bone marrow or peripheral blood samples rK39 immunochromatographic rapid test performed on serum sample Exclusion Criteria: pregnancy HIV infection chronic diseases such as diabetes mellitus,kidney, liver or cardiac diseases, schistosomiasis, malaria or tuberculosis immune disorders or use of drugs which interferes with the immune response treatment with drugs with increased risk for toxicity associated with the study drugs exposure to antileishmanial drugs during the past six months I.V. drug users episodes of visceral leishmaniasis relapse hypersensibility to the study drugs difficulties for accomplishing the follow-up schedule any of the following clinical signs of laboratory abnormalities: hepatic encephalopathy, generalized edema, toxemic individuals, severe malnutrition, jaundice, abnormal serum creatinine, bilirubin, INR > 2,0, platelet count < 20000/mm3
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Carlos HN Costa, MD PhD
Organizational Affiliation
Federal University of Piaui
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Dorcas L Costa, MD PhD
Organizational Affiliation
Federal University of Piaui
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Ana LT Rabello, MD PhD
Organizational Affiliation
Centro de Pesquisas Rene Rachou - Fiocruz - Minas Gerais
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Silvio FG de Carvalho, MD PhD
Organizational Affiliation
Montes Claros State University - Unimontes
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Andrea L de Carvalho, MD
Organizational Affiliation
Hospital Infantil Joao Paulo II - FHEMIG
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Roque P de Almeida, MD PhD
Organizational Affiliation
Federal University of Sergipe
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Fabiana P Alves, MD PhD
Organizational Affiliation
Drugs for Neglected Diseases
Official's Role
Study Director
First Name & Middle Initial & Last Name & Degree
Gustavo AS Romero, MD PhD
Organizational Affiliation
University of Brasilia
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Robério D Leite, MD, PhD
Organizational Affiliation
Hospital São José de Doenças Infecciosas, Secretaria de Saúde do Estado do Ceará.
Official's Role
Principal Investigator
Facility Information:
Facility Name
Hospital Universitário da Universidade Federal de Sergipe
City
Sergipe
State/Province
Aracaju
ZIP/Postal Code
49060-100
Country
Brazil
Facility Name
Hospital São José de Doenças Infecciosas
City
Fortaleza
State/Province
Ceará
ZIP/Postal Code
60455610
Country
Brazil
Facility Name
Hospital Infantil João Paulo II - FHEMIG
City
Belo Horizonte
State/Province
Minas Gerais
ZIP/Postal Code
30130-110
Country
Brazil
Facility Name
Hospital Universitário Clemente de Faria - Universidade Estadual de Montes Claros
City
Montes Claros
State/Province
Minas Gerais
ZIP/Postal Code
39401-002
Country
Brazil
Facility Name
Hospital de Doencas Infecto Contagiosas - HDIC
City
Teresina
State/Province
Piaui
ZIP/Postal Code
64001450
Country
Brazil

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
28662034
Citation
Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, Rabello A, de Carvalho AL, Sousa AQ, Leite RD, Lima SS, Amaral TA, Alves FP, Rode J; Collaborative LVBrasil Group. Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. PLoS Negl Trop Dis. 2017 Jun 29;11(6):e0005706. doi: 10.1371/journal.pntd.0005706. eCollection 2017 Jun.
Results Reference
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Efficacy and Safety Study of Drugs for Treatment of Visceral Leishmaniasis in Brazil

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