Human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosoma brucei
gambiense is a fatal disease. Current treatment options for patients with second-stage
disease are toxic, ineffective, or impractical. We assessed the efficacy and safety
of nifurtimox-eflornithine combination therapy (NECT) for second-stage disease compared
with the standard eflornithine regimen.
A multicentre, randomised, open-label, active control, phase III, non-inferiority
trial was done at four HAT treatment centres in the Republic of the Congo and the
Democratic Republic of the Congo. Patients aged 15 years or older with confirmed second-stage
T b gambiense infection were randomly assigned by computer-generated randomisation
sequence to receive intravenous eflornithine (400 mg/kg per day, every 6 h; n=144)
for 14 days or intravenous eflornithine (400 mg/kg per day, every 12 h) for 7 days
with oral nifurtimox (15 mg/kg per day, every 8 h) for 10 days (NECT; n=143). The
primary endpoint was cure (defined as absence of trypanosomes in body fluids and a
leucocyte count </=20 cells per muL) 18 months after treatment. Efficacy analyses
were done in the intention-to-treat (ITT), modified ITT, and per-protocol (PP) populations.
The non-inferiority margin for the difference in cure rates was defined as 10%. This
study is registered with ClinicalTrials.gov, number NCT00146627.
One patient from the eflornithine group absconded after receiving the first dose,
without any type of assessment done, and was excluded from all analyses. In the ITT
population, 131 (91.6%) of 143 patients assigned to eflornithine and 138 (96.5%) of
143 patients assigned to NECT were cured at 18 months (difference -4.9%, one-sided
95% CI -0.3; p<0.0001). In the PP population, 122 (91.7%) of 133 patients in the eflornithine
group and 129 (97.7%) of 132 in the NECT group were cured at 18 months (difference
-6.0%, one-sided 95% CI -1.5; p<0.0001). Drug-related adverse events were frequent
in both groups; 41 (28.7%) patients in the eflornithine group and 20 (14.0%) in the
NECT group had major (grade 3 or 4) reactions, which resulted in temporary treatment
interruption in nine and one patients, respectively. The most common major adverse
events were fever (n=18), seizures (n=6), and infections (n=5) in the eflornithine
group, and fever (n=7), seizures (n=6), and confusion (n=2) in the NECT group. There
were four deaths, which were regarded as related to study drug (eflornithine, n=3;
NECT, n=1).
The efficacy of NECT is non-inferior to that of eflornithine monotherapy. Since this
combination treatment also presents safety advantages, is easier to administer (ie,
infusion every 12 h for 7 days vs every 6 h for 14 days), and potentially protective
against the emergence of resistant parasites, it is suitable for first-line use in
HAT control programmes.
Médecins Sans Frontières (Dutch section), Médecins Sans Frontières International,
and the Drugs for Neglected Diseases Initiative.