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

Transcrição

1 Safety of available treatments for visceral leishmaniasis in Brazil: results from the LV Brasil trial Joelle Rode 1, Dorcas Lamounier Costa 2, Carlos Henrique Nery Costa 2, Roque Pacheco de Almeida 3, Enaldo Viera de Melo 3, Sílvio Fernando Guimarães de Carvalho 4, Ana Rabello 5, Andréa Lucchesi de Carvalho 6, Anastácio de Queiroz Sousa 7, Robério Dias Leite 7, Simone Soares Lima 8, Thais Alves Amaral 9, Fabiana Piovesan Alves 10, Gustavo Adolfo Sierra Romero 11 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 Funding: Ministry of Health of Brazil (CT/FINEP/MS/SCTIEDECIT CT-SAÚDE and FNS); Ministry of Science and Technology of Brazil (grants: / and /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.

2 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 NCT ). Interventions: Antimoniate of N-methyl glucamine (Glucantime, Sanofi-Aventis) 20mg Sb +5 /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 +5 /Kg/d I.V. x 10 d.

3 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) (-26.3 to - 1.5) p= (-11.6 to 14.4) p= 0.83 Absolute number of AE Median of AE per participant (P25- P75) 2 (1-4) Definitive treatment suspension % (n) 7.7 (16/208) Early withdrawal rate due to occurrence of AE/SAE - % (n/total) 13.5 (15/111) 2 (1-3) p= (1/143) p= (1/109) P< (1-3) p= (12/217) p= (10/112) P= (29/568) 7.8 (26/332) 6th World Congress on Leishmaniasis - 16th - 20th May 2017

4 Frequency and proportion of treatment-related AEs per system organ class and intervention SOC MA LAMB LAMB + MA Total Total number of AEs (100%) Laboratory biochemistry n 44 (21.2) 32 (22.4) 58 (26.7) 134 (23.6) Gastrointestinal n General/ systemic disorders n 54 (26.0) 33 (15.9) 28 (19.6) 34 (23.8) 34 (15.7) 44 (20.3) 116 (20.4) 111 (19.5) Laboratory hematology n 21 (10.1) 24 (16.8) 34 (15.7) 79 (13.9) Cardiovascular n (% ) Cutaneous n Administration site conditions n 17 (8.2) 12 (5.8) 12 (5.8) 4 (2.8) 5 (3.5) 4 (2.8) 15 (6.9) 9 (4.1) 9 (4.1) 36 (6.3) 26 (4.6) 25 (4.4)

5 Description of treatment-related SAEs Description of SAE n MA LAMB LAMB + MA Total Total number of SAE 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) (1.4) Potassium reduction - 1 (4.5) - 1 (1.4) Generalized oedema - 1 (4.5) - 1 (1.4) Convulsion 1 (4.8) (1.4) Sepsis 1 (4.8) (1.4) Diarrhoea - 1 (4.5) - 1 (1.4) Dyspnoea - 1 (4.5) - 1 (1.4) * There was no difference in the % of patients receiving a transfusion between the arms.

6 Conclusions 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