Three Drug Combinations for Late-Stage Trypanosoma brucei gambiense Sleeping Sickness: A Randomized Clinical Trial in Uganda (original) (raw)
Related papers
2007
Background: Human African trypanosomiasis caused by Trypanosoma brucei gambiense is a fatal disease. Current treatment options for patients with second-stage disease are either highly toxic or impracticable in field conditions. We compared the efficacy and safety of the nifurtimox-eflornithine drug combination with the standard eflornithine regimen for the treatment of second stage disease. Methods: A randomized, open-label, active-control, phase III clinical trial comparing 2 arms was conducted at the Sleeping Sickness Treatment Center, which was run by Médecins Sans Frontières, in Nkayi, Bouenza Province, Republic of Congo. Patients were screened for inclusion and randomly assigned to receive eflornithine alone (400 mg/kg per day given intravenously every 6 h for 14 days) or eflornithine (400 mg/kg per day given intravenously every 12 h for 7 days) plus nifurtimox (15 mg/kg per day given orally every 8 h for 10 days). Patients were observed for 18 months. The study’s outcomes were cure and adverse events attributable to treatment. Results: A total of 103 patients with second-stage disease were enrolled. Cure rates were 94.1% for the eflornithine group and 96.2% for the nifurtimox-eflornithine group. Drug reactions were frequent in both arms, and severe reactions affected 25.5% of patients in the eflornithine group and 9.6% of those in the nifurtimox-eflornithine group, resulting in 2 and 1 treatment suspensions, respectively. There was 1 death in the eflornithine arm and no deaths in the nifurtimox-eflornithine arm. Conclusions: The nifurtimox-eflornithine combination appears to be a promising first-line therapy for second-stage sleeping sickness. If our findings are corroborated by ongoing findings from additional sites (a multicenter extension of this study), the new nifurtimox-eflornithine combination therapy will mark a major and multifaceted advance over current therapies.
2009
Background: 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. Methods: 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 efl ornithine (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 μL) 18 months after treatment. Efficacy analyses were done in the intention-to-treat (ITT), modifi ed ITT, and per-protocol (PP) populations. The non-inferiority margin for the diff erence in cure rates was defi ned as 10%. This study is registered with ClinicalTrials.gov, number NCT00146627. Findings: One patient from the efl ornithine 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 efl ornithine 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 efl ornithine 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). Interpretation: 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 fi rst-line use in HAT control programmes.
Cureus, 2021
Human African trypanosomiasis (HAT), or sleeping sickness disease, is an infection caused mainly by Trypanosoma brucei gambiense-human African trypanosomiasis (g-HAT) and is transmitted by tsetse flies. The disease goes through two stages: hemolymphatic and meningo-encephalic phases. The treatment for the second stage has changed from melarsoprol or eflornithine to nifurtimox-eflornithine combination therapy (NECT) and fexinidazole. We aimed to systematically review the literature on the efficacy and toxicity of fexinidazole and NECT. We used PubMed advanced strategy and Google Scholar databases, including clinical trials and observational studies on humans in the last 20 years in the English literature. Applying the inclusion/exclusion criteria, we reviewed eight studies. We used Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocol. For assessing bias, we used the Cochrane Collaboration's tool for risk assessment of the clinical trials and the Robins-I tool for the observational studies. Overall, the clinical trials showed that NECT was non-inferior to eflornithine. The proportion of patients discharged alive is higher in patients treated with NECT vs. patients treated with eflornithine. Gastrointestinal complaints are a common side effect of NECT therapy, while fearful but relatively rare convulsions can also occur. The main limitation among the studies of NECT was the lack of blinding because most of them were open-label. Fexinidazole, the new oral medication showed is effective and safe for the treatment of g-HAT infection. Because of their convenience, fexinidazole is preferred over NECT therapy, oral vs. IV infusion in the first and second stages of the disease. Compared to older therapies, fexinidazole and NECT are more effective and safer than eflornithine and melarsoprol monotherapy.
PLOS ONE, 2021
Chagas disease is a neglected illness caused by Trypanosoma cruzi and its treatment is done only with two drugs, nifurtimox and benznidazole. However, both drugs are ineffective in the chronic phase, in addition to causing serious side effects. This context of therapeutic limitation justifies the continuous research for alternative drugs. Here, we study the in vitro trypanocidal effects of the non-steroidal anti-inflammatory drug nimesulide, a molecule that has in its chemical structure a toxicophoric nitroaromatic group (NO2). The set of results obtained in this work highlights the potential for repurposing nimesulide in the treatment of this disease that affects millions of people around the world.
Chemotherapy for second-stage human African trypanosomiasis: drugs in use
The Cochrane library, 2021
BackgroundHuman African trypanosomiasis, or sleeping sickness, is a severe disease affecting people in the poorest parts of Africa. It is usually fatal without treatment. Conventional treatments require days of intravenous infusion, but a recently developed drug, fexinidazole, can be given orally. Another oral drug candidate, acoziborole, is undergoing clinical development and will be considered in subsequent editions. ObjectivesTo evaluate the effectiveness and safety of currently used drugs for treating second‐stage Trypanosoma brucei gambiense trypanosomiasis (gambiense human African trypanosomiasis, g‐HAT).Search methodsOn 14 May 2021, we searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, Latin American and Caribbean Health Science Information database, BIOSIS, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We also searched reference lists of included studies, contacted researchers working in the field, and contacted relevant organizations.Selection criteriaEligible studies were randomized controlled trials that included adults and children with second‐stage g‐HAT, treated with anti‐trypanosomal drugs currently in use.Data collection and analysisTwo review authors extracted data and assessed risk of bias; a third review author acted as an arbitrator if needed. The included trial only reported dichotomous outcomes, which we presented as risk ratio (RR) or risk difference (RD) with 95% confidence intervals (CI). Main resultsWe included one trial comparing fexinidazole to nifurtimox combined with eflornithine (NECT). This trial was conducted between October 2012 and November 2016 in the Democratic Republic of the Congo and the Central African Republic, and included 394 participants. The study reported on efficacy and safety, with up to 24 months' follow‐up. We judged the study to be at low risk of bias in all domains except blinding; as the route of administration and dosing regimens differed between treatment groups, participants and personnel were not blinded, resulting in a high risk of performance bias. Mortality with fexinidazole may be higher at 24 months compared to NECT. There were 9/264 deaths in the fexinidazole group and 2/130 deaths in the NECT group (RR 2.22, 95% CI 0.49 to 10.11; 394 participants; low‐certainty evidence). None of the deaths were related to treatment.Fexinidazole likely results in an increase in the number of people relapsing during follow‐up, with 14 participants in the fexinidazole group (14/264) and none in the NECT group (0/130) relapsing at 24 months (RD 0.05, 95% CI 0.02 to 0.08; 394 participants; moderate‐certainty evidence). We are uncertain whether there is any difference between the drugs regarding the incidence of serious adverse events at 24 months. (31/264 with fexinidazole and 13/130 with NECT group at 24 months). Adverse events were common with both drugs (247/264 with fexinidazole versus 121/130 with NECT), with no difference between groups (RR 1.01, 95% CI 0.95 to 1.06; 394 participants; moderate‐certainty evidence). Authors' conclusionsOral treatment with fexinidazole is much easier to administer than conventional treatment, but deaths and relapse appear to be more common. However, the advantages or an oral option are considerable, in terms of convenience, avoiding hospitalisation and multiple intravenous infusions, thus increasing adherence.