Universidade Federal do Piauí, Hospital de Doenças Tropicais Natan Portela, Teresina, Piauí, Brazil 3

Safety of available treatments for visceral leishmaniasis

in Brazil: results from the “LV Brasil” trial

Joelle Rode1_{, Dorcas Lamounier Costa}2_{, Carlos Henrique Nery Costa}2_{, Roque Pacheco de Almeida}3_{, Enaldo Viera}

de Melo3_{, Sílvio Fernando Guimarães de Carvalho}4_{, Ana Rabello}5_{, Andréa Lucchesi de Carvalho}6_{, Anastácio de}

Queiroz Sousa7_{, Robério Dias Leite}7_{, Simone Soares Lima}8_{, Thais Alves Amaral}9_{, Fabiana Piovesan Alves}10_,

Gustavo Adolfo Sierra Romero11

1_{Drugs for Neglected Diseases initiative (DNDi), Rio de Janeiro, Rio de Janeiro, Brazil}

2_{Universidade Federal do Piauí, Hospital de Doenças Tropicais Natan Portela, Teresina, Piauí, Brazil} 3_{Universidade Federal de Sergipe, Hospital Universitário, Aracaju, Sergipe, Brazil}

4_{Departamento de Doenças Infecciosas, Hospital Universitário Clemente de Faria, Universidade Estadual de Montes}

Claros, Montes Claros, Minas Gerais, Brazil

5_{Laboratório de Pesquisa Clínica, e Políticas Públicas em Doenças Infecciosas e Parasitárias, Centro de Pesquisas}

René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil

6_{Hospital Infantil João Paulo II, Fundação Hospitalar do Estado de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil} 7_{Universidade Federal do Ceará, Hospital São José de Doenças Infecciosas, Fortaleza, Ceará, Brazil}

8_{Universidade Federal do Piauí – Hospital Infantil Lucídio Portela, Teresina, Piauí, Brazil}

9_{Plataforma de Pesquisa Clínica, Vice-Presidência de Pesquisa e Laboratórios de Referência, Fundação Oswaldo Cruz,}

Rio de Janeiro, Rio de Janeiro, Brazil

10_{Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland}

11_{Núcleo de Medicina Tropical, Universidade de Brasília, Brasília, Distrito Federal, Brazil}

6th _{World Congress on Leishmaniasis - 16}th _{- 20}th _{May 2017}

Funding: Ministry of Health of Brazil (CT/FINEP/MS/SCTIEDECIT–CT-SAÚDE and FNS); Ministry of Science and Technology of Brazil (grants: 420580/2013-1 and 520029/2009-7); Department for International Development (DFID), UK; Spanish

Agency for International Development Cooperation (AECID), Spain; Médecins Sans Frontières, International; and private donor in Brazil.

Rationale and objectives



In order to provide evidence for the rational use of visceral

leishmaniasis (VL) treatments, a multicenter, randomized, open label,

controlled trial was conducted to assess the safety and efficacy of the

treatments recommended for VL in Brazil, as well as a combination

treatment of Glucantime

®

and AmBisome

®

(ClinicalTrials.gov

identification number NCT01310738).



Interventions:



Antimoniate of N-methyl glucamine (Glucantime®, Sanofi-Aventis) 20mg

Sb

_{/Kg/d, I.V. X 20 d (ACTIVE COMPARATOR).}



Amphotericin B deoxycholate (Anforicin B®, Cristália) - 1mg/kg/d, I.V. x

14 d.



Liposomal amphotericin B (AmBisome®, Gilead) - 3mg/kg/d, I.V. x 7 d.

Liposomal amphotericin B (AmBisome®, Gilead) 10mg/Kg I.V. single dose

+ AntimoniateN -methyl glucamine (Glucantime®, Sanofi-Aventis), 20mg

Sb

_{/Kg/d I.V. x 10 d.}

Safety results

568/1,774 (32.6%) treatment-related AEs. Among them 124 SAEs, of which

71 (57.3%) treatment-related. 2 deaths: 1 treatment-related (MA), 1 not

related (LAMB+MA).

MA (111)

(comparator) LAMB (109)

LAMB+MA

(112) Total (332) % of patients with at least one AE (n) 74.8 (83) 65.1 (71) 75.9 (85) 71.2 (239)

% of patients with at least one SAE (n) 18.0 (20) 17.4 (19) 24.1 (27) 19.9 (66)

% of patients with grade 3 or 4 AE (n) 41.4 (46) 27.5 (30) 42.8 (48) 37.3 (124)

Difference in % of patients with AE grade 3 or 4 (95% CI) 13.9 (26.3 to -1.5) p= 0.029 1.4 (-11.6 to 14.4) p= 0.83 Absolute number of AE 208 143 217 568

Median of AE per participant

(P25-P75) 2 (1 - 4)

2 (1 - 3)

p=0.045

2 (1 - 3)

p= 0.982 Definitive treatment suspension % (n) 7.7 (16/208) 0.7 (1/143)

p=0.003

5.5 (12/217)

p=0.369 5.1 (29/568)

Early withdrawal rate due to

occurrence of AE/SAE - % (n/total)

0.92 (1/109)

P<0.001

8.9 (10/112)

P=0.278 7.8 (26/332) 6th World Congress on Leishmaniasis - 16th - 20th May 2017

Frequency and proportion of treatment-related AEs

per system organ class and intervention

SOC

MA

LAMB

LAMB + MA

Total

Total number of AEs (100%) 208 143 217 568

Laboratory biochemistry n (%) 44 (21.2) 32 (22.4) 58 (26.7) 134 (23.6) Gastrointestinal n (%) 54 (26.0) 28 (19.6) 34 (15.7) 116 (20.4)

General/ systemic disorders n (%) 33 (15.9) 34 (23.8) 44 (20.3) 111 (19.5) Laboratory hematology n (%) 21 (10.1) 24 (16.8) 34 (15.7) 79 (13.9) Cardiovascular n (% ) 17 (8.2) 4 (2.8) 15 (6.9) 36 (6.3) Cutaneous n (%) 12 (5.8) 5 (3.5) 9 (4.1) 26 (4.6)

Administration site conditions n (%) 12 (5.8) 4 (2.8) 9 (4.1) 25 (4.4)

Description of SAE n (%) MA LAMB LAMB + MA Total

Total number of SAE _{21 22 28 71}

Grade 3/4 increase of pancreatic and/or liver

enzymes 6 (28.6) 1 (4.5) 5 (17.8) 12 (16.9)

Cardiac toxicity 4 (19.0) - 4 (14.3) 8 (11.3)

Anaemia (alone or associated with other

abnormal haematological parameters) * 3 (14.3) 9 (40.9) 11 (39.3) 23 (32.4) Neutropaenia or thrombocytopaenia _{3 (14.3) 3 (13.6) 3 (10.7) 9 (12.7)} Phlebitis / cellulitis 1 (4.8) 1 (4.5) 3 (10.7) 5 (7.0) Fever - 4 (18.2) - 4 (5.6) Allergic reaction 1 (4.8) - 2 (7.1) 3 (4.2) Cutaneous rash 1 (4.8) - - 1 (1.4) Potassium reduction - 1 (4.5) - 1 (1.4) Generalized oedema - 1 (4.5) - 1 (1.4) Convulsion 1 (4.8) - - 1 (1.4) Sepsis 1 (4.8) - - 1 (1.4) Diarrhoea - 1 (4.5) - 1 (1.4) Dyspnoea - 1 (4.5) - 1 (1.4)

Description of treatment-related SAEs

6th_{World Congress on Leishmaniasis - 16}th_{- 20}th_{May 2017}

•

Overall 71.2% of patients presented at least one treatment-related AE,

mainly alteration of biochemistry parameters, gastrointestinal disorders,

systemic disorders and haematological parameter alterations.

•

19.9% of patients presented at least one treatment-related SAE, mainly

anaemia (higher in interventions with LAMB) and haematological

parameter alterations, increase of pancreatic and/or liver enzymes and

cardiac toxicity (higher in interventions with MA).

•

LAMB monotherapy was statistically safer than MA regarding frequency of

treatment-related AEs, proportion of patients presenting at least one

severe AE, and proportion of AEs resulting in definitive treatment

suspension and need for rescue treatment.

•

The better safety profile of LAMB in monotherapy suggests it would be a

more suitable first line treatment for VL in Brazil.

•

Detailed safety results will contribute to better VL case management and

guidance for treatment recommendation adoption by health care providers

Conclusions