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

Multicentric Efficacy and Safety Study of Antileishmanial Drugs for Treatment of Visceral Leishmaniasis in Brazil

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.

Study Overview

• Status: Terminated
• Conditions: Visceral Leishmaniasis
• Intervention / Treatment: Drug: Antimoniate of N-methylglucamine; Drug: Antimoniate of N-methylglucamine; Drug: Liposomal amphotericin B; Drug: Liposomal amphotericin B; Drug: amphotericin B deoxycholate

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.

• Study Type: Interventional
• Enrollment (Actual): 378
• Phase: Phase 4

Contacts and Locations

Study Locations

• Brazil
  • Aracaju
    • Sergipe, Aracaju, Brazil, 49060-100
      • Hospital Universitário da Universidade Federal de Sergipe
  • Ceará
    • Fortaleza, Ceará, Brazil, 60455610
      • Hospital São José de Doenças Infecciosas
  • Minas Gerais
    • Belo Horizonte, Minas Gerais, Brazil, 30130-110
      • Hospital Infantil João Paulo II - FHEMIG
    • Montes Claros, Minas Gerais, Brazil, 39401-002
      • Hospital Universitário Clemente de Faria - Universidade Estadual de Montes Claros
  • Piaui
    • Teresina, Piaui, Brazil, 64001450
      • Hospital de Doencas Infecto Contagiosas - HDIC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 6 months to 50 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Meglumine antimoniate; Antimoniate of N-methylglucamine 20mg/kg/d, I.V. for 20 consecutive days.	Drug: Antimoniate of N-methylglucamine; Antimoniate of N-methyl glucamine 20mg/kg/d of pentavalent antimonial, I.V. for 20 consecutive days.; Other Names: Glucantime; Drug: Antimoniate of N-methylglucamine; 20mg/kg/d of pentavalent antimonial I.V. for 10 days; Other Names: Glucantime
Experimental: Liposomal Amphotericin B; Liposomal amphotericin B 3mg/kg/d I.V. for 7 consecutive days.	Drug: Liposomal amphotericin B; 3mg/kg/d, I.V. for 7 consecutive days.; Other Names: AmBisome; Drug: Liposomal amphotericin B; 10mg/kg/d, I.V. single dose.; Other Names: AmBisome
Experimental: Amphotericin B; 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.	Drug: amphotericin B deoxycholate; 1mg/kg/d, I.V. for 14 consecutive days.; Other Names: Fungizone; Anforicin B
Experimental: Combination therapy; 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.	Drug: Antimoniate of N-methylglucamine; Antimoniate of N-methyl glucamine 20mg/kg/d of pentavalent antimonial, I.V. for 20 consecutive days.; Other Names: Glucantime; Drug: Antimoniate of N-methylglucamine; 20mg/kg/d of pentavalent antimonial I.V. for 10 days; Other Names: Glucantime; Drug: Liposomal amphotericin B; 3mg/kg/d, I.V. for 7 consecutive days.; Other Names: AmBisome; Drug: Liposomal amphotericin B; 10mg/kg/d, I.V. single dose.; Other Names: AmBisome

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement rate	Fever disappearing, stable or improving hematological lab abnormalities plus any spleen size reduction.	30 days
Relapse rate	Reappearing of signs and symptoms after any improvement observed after treatment, during the six months follow-up period.	(6 months post treatment) After treatment until the sixth month of follow-up
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.	During (day one) and within the six months follow-up
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.	During (day one) treatment and within the six months follow-up

Collaborators and Investigators

• Sponsor: University of Brasilia
• Collaborators: Ministry of Health, Brazil; Conselho Nacional de Desenvolvimento Científico e Tecnológico; Drugs for Neglected Diseases
• Investigators: Principal Investigator: Carlos HN Costa, MD PhD, Federal University of Piaui; Principal Investigator: Dorcas L Costa, MD PhD, Federal University of Piaui; Principal Investigator: Ana LT Rabello, MD PhD, Centro de Pesquisas Rene Rachou - Fiocruz - Minas Gerais; Principal Investigator: Silvio FG de Carvalho, MD PhD, Montes Claros State University - Unimontes; Principal Investigator: Andrea L de Carvalho, MD, Hospital Infantil João Paulo II - FHEMIG; Principal Investigator: Roque P de Almeida, MD PhD, Federal University of Sergipe; Study Director: Fabiana P Alves, MD PhD, Drugs for Neglected Diseases; Study Chair: Gustavo AS Romero, MD PhD, University of Brasilia; Principal Investigator: Robério D Leite, MD, PhD, Hospital São José de Doenças Infecciosas, Secretaria de Saúde do Estado do Ceará.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): October 1, 2014
• Study Completion (Actual): February 1, 2015

Study Registration Dates

• First Submitted: March 7, 2011
• First Submitted That Met QC Criteria: March 7, 2011
• First Posted (Estimate): March 8, 2011

Study Record Updates

• Last Update Posted (Actual): September 5, 2017
• Last Update Submitted That Met QC Criteria: August 31, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: Visceral leishmaniasis; Leishmania infantum; Leishmania chagasi
• Additional Relevant MeSH Terms: Skin Diseases; Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Skin Diseases, Parasitic; Skin Diseases, Infectious; Euglenozoa Infections; Leishmaniasis; Leishmaniasis, Visceral; Anti-Infective Agents; Gastrointestinal Agents; Anti-Bacterial Agents; Antifungal Agents; Antiprotozoal Agents; Antiparasitic Agents; Amebicides; Cholagogues and Choleretics; Deoxycholic Acid; Amphotericin B; Liposomal amphotericin B; Amphotericin B, deoxycholate drug combination; Meglumine Antimoniate
• Other Study ID Numbers: LVBrasil_2007; 559819/2010-2 (Other Grant/Funding Number: CNPq - Brazil); 108042500 (Other Grant/Funding Number: Finaciadora de Estudos e Projetos - FINEP - Brazil); CAAE 0973.1.000.245-10 (Other Identifier: Brazilian National Ethics Council)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided