Nifurtimox-eflornithine combination therapy for second-stage African Trypanosoma brucei gambiense trypanosomiasis: a multicentre, randomised, phase III, non-inferiority trial. Three drug combinations for late-stage Trypanosoma brucei gambiense sleeping sickness: a randomized clinical trial in Uganda. Efficacy of new, concise schedule for melarsoprol in treatment of sleeping sickness caused by Trypanosoma brucei gambiense: a randomised trial. Equivalence trial of melarsoprol and nifurtimox monotherapy and combination therapy for the treatment of second-stage Trypanosoma brucei gambiense sleeping sickness. Randomized controlled trial of three regimens of melarsoprol in the treatment of Trypanosoma brucei gambiense trypanosomiasis. Trial of prednisolone for prevention of melarsoprol-induced encephalopathy in gambiense sleeping sickness. Short-course eflornithine in Gambian trypanosomiasis: a multicentre randomized controlled trial. The pharmacokinetics of eflornithine (alpha-difluoromethylornithine) in patients with late-stage T.b. gambiense sleeping sickness.
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. Our objective was to compare the efficacy and safety of three drug combinations for the treatment of late-stage human African trypanosomiasis caused by Trypanosoma brucei gambiense.
                This trial was a randomized, open-label, active control, parallel clinical trial comparing three arms.
                The study took place at the Sleeping Sickness Treatment Center run by Médecins Sans Frontières at Omugo, Arua District, Uganda
                Stage 2 patients diagnosed in Northern Uganda were screened for inclusion and a total of 54 selected.
                Three drug combinations were given to randomly assigned patients: melarsoprol-nifurtimox (M+N), melarsoprol-eflornithine (M+E), and nifurtimox-eflornithine (N+E). Dosages were uniform: intravenous (IV) melarsoprol 1.8 mg/kg/d, daily for 10 d; IV eflornithine 400 mg/kg/d, every 6 h for 7 d; oral nifurtimox 15 (adults) or 20 (children <15 y) mg/kg/d, every 8 h for 10 d. Patients were followed up for 24 mo.
                Outcomes were cure rates and adverse events attributable to treatment.
                Randomization was performed on 54 patients before enrollment was suspended due to unacceptable toxicity in one of the three arms. Cure rates obtained with the intention to treat analysis were M+N 44.4%, M+E 78.9%, and N+E 94.1%, and were significantly higher with N+E (p = 0.003) and M+E (p = 0.045) than with M+N. Adverse events were less frequent and less severe with N+E, resulting in fewer treatment interruptions and no fatalities. Four patients died who were taking melarsoprol-nifurtimox and one who was taking melarsoprol-eflornithine.
                The N+E combination appears to be a promising first-line therapy that may improve treatment of sleeping sickness, although the results from this interrupted study do not permit conclusive interpretations. Larger studies are needed to continue the evaluation of this drug combination in the treatment of T. b. gambiense sleeping sickness. African trypanosomiasis is a fatal disease caused by protozoan parasites of the species Trypanosoma brucei. The disease has reached epidemic dimensions in various countries of central Africa. Treatment of the second stage is long and complicated, and is hampered by severe adverse reactions to the first-line drug, melarsoprol. Despite these problems, melarsoprol is likely to remain the drug of choice for the next decade. We therefore did a randomised trial comparing the standard treatment schedule with a new, concise regimen.
                The safety and efficacy of the new schedule were assessed in patients presenting to a hospital in Kwanza Norte, Angola with sleeping sickness. The control group followed the 26-day standard Angolan schedule of three series of four daily injections of melarsoprol at doses increasing from 1.2 to 3.6 mg/kg within each series, with a 7-day interval between series. The new treatment schedule comprised 10 daily injections of 2.2 mg/kg. Primary outcomes assessed were elimination of parasites, deaths attributed to treatment, and rate of encephalopathy. Analysis was by intention to treat.
                Of 767 patients with second-stage disease, 500 were enrolled: 250 were assigned the standard schedule, and 250 the new schedule. 40 patients on the standard schedule and 47 on the new schedule had adverse events which resulted in treatment disruption or withdrawal. 50 patients on the standard regimen deviated or withdrew from treatment, compared with two on the new regimen. Parasitological cure 24 h after treatment was 100% in both groups; there were six deaths (all due to encephalopathy) 30 days after treatment in each group. The number of patients with encephalopathic syndromes was also the same in each group (14). Skin reactions were more common with the new treatment, but all could be resolved by additional medication or withdrawal of treatment.
                Considering the economic and practical advantages of the new 10-day schedule over the standard 26-day treatment schedule, and the similarity of treatment outcome, the new schedule is a useful alternative to the present standard, especially in epidemic situations and in locations with limited resources. Treatment of second-stage sleeping sickness relies mainly on melarsoprol. Nifurtimox has been successfully used to cure melarsoprol-refractory sleeping sickness caused by Trypanosoma brucei gambiense infection.
                An open, randomized trial was conducted to test for equivalence between the standard melarsoprol regimen and 3 other regimens, as follows: standard melarsoprol therapy (3 series of 3.6 mg/kg/day intravenously [iv] for 3 days, with 7-day breaks between the series); 10-day incremental-dose melarsoprol therapy (0.6 mg/kg iv on day 1, 1.2 mg/kg iv on day 2, and 1.8 mg/kg iv on days 3-10); nifurtimox monotherapy for 14 days (5 mg/kg orally 3 times per day); and consecutive 10-day melarsoprol-nifurtimox combination therapy (0.6 mg/kg iv melarsoprol on day 1, 1.2 mg/kg iv melarsoprol on day 2, and 1.2 mg/kg/day iv melarsoprol combined with oral 7.5 mg/kg nifurtimox twice a day on days 3-10). Primary outcomes were relapse, severe adverse events, and death attributed to treatment.
                A total of 278 patients were randomized. The frequency of adverse events was similar between the standard melarsoprol regimen and the other regimens. Encephalopathic syndromes occurred in all groups and caused all deaths that were likely due to treatment. Relapses (n=48) were observed only with the 3 monotherapy regimens.
                A consecutive 10-day low-dose melarsoprol-nifurtimox combination is more effective than the standard melarsoprol regimen. A total of 389 patients with late-stage Trypanosoma brucei gambiense trypanosomiasis were enrolled in a randomized controlled trial comparing the efficacy and toxicity of three regimens of melarsoprol: regimen A, 3.6 mg/kg (max. 180 mg) for all i.v. injections, given as three series of three injections separated by 1-week intervals; regimen B, 10 consecutive daily i.v. injections of 2.16 mg/kg; or regimen C, three series of three i.v. injections separated by 1-week intervals, but with graded dosing (1.8, 2.16, 2.52, 2.52, 2.88, 3.24, then 3.6 mg/kg for the last three injections). After treatment, patients were followed with half-yearly lumbar punctures for 2 years. During treatment, convulsions were significantly more common in patients allocated to the graded dosing regimen (7/70 [10.0%] vs. 11/319 [3.4%], P = 0.03). The 2-year probability of relapse was 5.4%, 7.4% and 25.0% for regimens A, B and C respectively (P < 0.001). The new regimen of 10 daily injections of melarsoprol was as effective and had the same toxicity as the traditional regimen of three series of three injections at the full dose. Graded dosing, which was associated with a much lower efficacy and more frequent convulsions, should be abandoned. In a prospective randomised trial, 620 patients who had Trypanosoma brucei gambiense trypanosomiasis with central nervous system involvement were treated either with prednisolone plus melarsoprol or with melarsoprol only. 598 patients were evaluable: morbidity and death associated with melarsoprol-induced encephalopathy was reduced in patients who were given prednisolone. The two groups did not differ either in the incidence of other complications of melarsoprol therapy or in relapse rate after melarsoprol therapy. The cost of prednisolone would be outweighed by savings on the treatment of encephalopathies in such patients. A randomized controlled trial was conducted to determine whether 7 days of intravenous eflornithine (100 mg/kg every 6 h) was as effective as the standard 14-day regimen in the treatment of late-stage Trypanosoma brucei gambiense trypanosomiasis.
                A total of 321 patients (274 new cases, 47 relapsing cases) were randomized at four participating centres in Congo, Côte d'Ivoire, the Democratic Republic of the Congo, and Uganda to one of these treatment regimens and followed up for 2 years.
                Six patients died during treatment, one of whom was on the 7-day regimen, whereas the other five had been on the 14-day regimen (P = 0.2). The response to eflornithine differed markedly between Uganda and other countries. Among new cases in Uganda, the 2-year probability of cure was 73% on the 14-day course compared with 62% on the 7-day regimen (hazard ratio (HR) for treatment failure, 7-day versus 14-day regimen: 1.45, 95% CI: 0.7, 3.1, P = 0.3). Among new cases in Côte d'Ivoire, Congo, and the Democratic Republic of the Congo combined, the 2-year probability of cure was 97% on the 14-day course compared with 86.5% on the 7-day regimen (HR for treatment failure, 7-day vs 14-day: 6.72, 95% confidence interval (CI): 1.5, 31.0, P = 0.003). Among relapsing cases in all four countries, the 2-year probability of cure was 94% with 7 days and 100% with 14 days of treatment. Factors associated with a higher risk of treatment failure were: a positive lymph node aspirate (HR 4.1; 95% CI: 1.8-9.4), a cerebrospinal fluid (CSF) white cell count > or = 100/mm3 (HR 3.5; 95% CI: 1.1-10.9), being treated in Uganda (HR 2.9; 95% CI: 1.4-5.9), and CSF trypanosomes (HR 1.9; 95% CI: 0.9-4.1). Being stuporous on admission was associated with a lower risk of treatment failure (HR 0.18; 95% CI: 0.02-1.4) as was increasing age (HR 0.977; 95% CI: 0.95-1.0, for each additional year of age).
                The 7-day course of eflornithine is an effective treatment of relapsing cases of Gambian trypanosomiasis. For new cases, a 7-day course is inferior to the standard 14-day regimen and cannot be recommended. To investigate the plasma, cerebrospinal fluid (CSF) levels and pharmacokinetics of eflornithine (DFMO) in patients with late-stage T.b. gambiense sleeping sickness who were treated with an oral DFMO at 100 mg/kg or 125 mg/kg body weight every 6 h for 14 days.
                Plasma and CSF concentrations of DFMO were measured during day 10 and day 15 in patients following oral DFMO at 100 mg/kg (group I: n=12) and 125 mg/kg (group II: n=13) body weight every 6 h for 14 days. Clinical and parasitological assessments were performed at 24 h after the last dose of DFMO and at 12 months.
                Patients in each group had a good initial response, but relapse was observed in six patients (three patients for each group) during 12 months follow-up. Plasma DFMO concentrations did not increase proportionally to doses when the dose increased from 100 mg/kg to 125 mg/kg body weight given every 6 h (60-70% of the expected increase). In most cases, concentration-time profiles of DFMO in each group were best fit using a two-compartment open model with first-order input, with absorption lag-time and first-order elimination. Average trough (C(ss-min)) and average (C(ss-ave)) plasma DFMO concentrations during steady state varied between 189-448 nmol/ml and 234-528 nmol/ml, following 100 mg/kg and 125 mg/kg dose group, respectively. C(max), t(max) and AUC(0- infinity ) values following the last dose were 296-691 nmol/l, 2-3 h, and 2911-6286 nmol h/ml, respectively. V(z)/F, CL/F and t(1/2z) values were 0.47-2.66 l/kg, 0.064-0.156 l/h/kg, and 3.0-16.3 h, respectively. CSF concentrations at steady state varied between 22.3 nmol/ml and 64.7 nmol/ml. Patients who had treatment failure tended to have lower plasma and CSF DFMO concentrations than those who had successful treatment.
                Oral DFMO at the dose of 125 mg/kg body weight given every 6 h for 14 days may not produce adequate therapeutic plasma and CSF levels for patients with late-stage T.b. gambiense sleeping sickness.
Choice of therapy for second stage Gambiense HAT will continue to be determined by what is locally available, but eflornithine and NECT are likely to replace melarsoprol, with careful parasite resistance monitoring. We need research on reducing adverse effects of currently used drugs, testing different regimens, and experimental and clinical studies of new compounds, effective for both stages of the disease.