By Dean L. Winslow, MD, FACP, FIDSA

Professor of Medicine, Division of General Medical Disciplines, Division of Infectious Diseases and Geographic Medicine, Stanford University

Dr. Winslow reports no financial relationships relevant to this field of study.

SYNOPSIS: A randomized, controlled trial of E1224 (a ravuconazole prodrug) in different doses and durations was studied in adult patients with chronic indeterminate Chagas disease. Parasite clearance was observed in treated patients, but the response was transient in most patients.

SOURCE: Torrico F, Fascon J, Ortiz L, et al. Treatment of adult chronic indeterminate Chagas disease with benznidazole and three E1224 dosing regimens: A proof-of-concept, randomized, placebo-controlled trial. Lancet Infect Dis 2018 Jan 15: pii: S1473-3099(17)30538-8. [Epub ahead of print].

A proof-of-concept, double-blind, randomized, Phase II clinical trial was conducted in two outpatient units in Bolivia. During 2011-2012, 560 patients with chronic Chagas disease were screened and 231 were randomized. Patients were randomized 1:1:1:1:1 to oral E1224 high dose/eight weeks, low dose/eight weeks, short dose (four weeks E1224 followed by four weeks of placebo), benznidazole 5 mg/kg for 60 days, and placebo for eight weeks. The primary efficacy endpoint was parasitological clearance as assessed by polymerase chain reaction (PCR), and secondary endpoints included serologic response and changes in biomarkers.

Parasite clearance was observed with E1224 during treatment administration, but no sustained response was seen with either the low-dose or short-course treatment regimens. Thirteen of 45 (29%) patients treated with high-dose E1224 compared with four of 47 (9%) in the placebo group had sustained responses at 12-month follow up. In contrast, benznidazole had a rapid and sustained effect on parasite clearance, with 37 of 45 (82%) at 12-month follow up as assessed by PCR. Both E1224 and benznidazole were well tolerated, with reversible dose-dependent increase in liver enzymes seen in both E1224- and benznidazole-treated patients, but only six patients in the study (3%) developed treatment-emergent serious adverse events.

COMMENTARY

This well-designed, randomized, placebo-controlled, proof-of-concept study demonstrated that this new imidazole prodrug had modest in vivo activity as shown by dose-dependent suppression of parasitemia as assessed by PCR. However, it was disappointing that E1224 did not appear as active as benznidazole.

This follows fairly shortly after the publication of another disappointing randomized, placebo-controlled trial in which benznidazole, while showing parasitological clearance, had no clinical efficacy in the treatment of patients with different stages of Chagas cardiomyopathy.¹ However, the fact that E1224 demonstrated trypanosomal DNA reduction activity in vivo suggests that trials of E1224 in combination with benznidazole or nifurtimox should be conducted.

REFERENCE

1. Morillo CA, Marin-Neto JA, Avezum A, et al. Randomized trial of benznidazole for chronic Chagas’ cardiomyopathy. N Engl J Med 2015;373:1295-1306.