BACKGROUND
For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis.
METHODS
We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points.
RESULTS
Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy.
CONCLUSIONS
Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).
BACKGROUND
In settings with low pneumococcal conjugate vaccine (PCV) coverage, multi-age cohort mass campaigns could increase population immunity, and fractional dosing could increase affordability. We aimed to evaluate the effect of mass campaigns on nasopharyngeal pneumococcal carriage of Pneumosil (PCV10) in children aged 1-9 years in Niger.
METHODS
In this three-arm, open-label, cluster-randomised trial, 63 clusters of one to four villages in Niger were randomly assigned (3:3:1) using block randomisation to receive campaigns consisting of a single full dose of a 10-valent PCV (Pneumosil), a single one-fifth dose of Pneumosil, or no campaign. Independently sampled carriage surveys were done among 2268 households 6 months before and after vaccination, collecting nasopharyngeal swabs from healthy children for culture and serotyping; those with contraindication to nasopharyngeal swabbing were excluded. The primary outcome was nasopharyngeal carriage of vaccine-serotype pneumococcus. We tested whether vaccine-type carriage was reduced in full-dose versus control clusters; and whether fractional doses were non-inferior to full-doses (lower bound 95% CI more than -7·5%), using generalised estimating equations to analyse cluster summaries at baseline and follow-up, controlling for covariates to estimate risk differences and their 95% CIs. The study is registered with ClinicalTrials.gov (NCT05175014) and the Pan-African Clinical Trials Registry (PACTR20211257448484).
FINDINGS
Surveys were done between Dec 22, 2021, and March 18, 2022, and between Dec 12, 2022, and March 9, 2023. The vaccination campaign ran from June 15 to Aug 2, 2022. Participants' characteristics were consistent across surveys and groups. Pre-vaccination, vaccine-type carriage was 15·6% (149 of 955 participants) in the full-dose group, 17·9% (170 of 948) in the fractional-dose group, and 18·8% (60 of 320) in the control group. Post-vaccination, vaccine-type carriage was 4·6% (44 of 967) in the full-dose group, 8·0% (77 of 962) in the fractional-dose group, and 16·5% (53 of 321) in the control group. The primary analysis showed a risk difference of -16·2% (95% CI -28·6 to -3·0) between the full-dose group and control group (p=0·002 for superiority), and -3·8% (-6·1 to -1·6) between the full-dose group and fractional-dose group, meeting the non-inferiority criteria. No adverse events were judged to be related to vaccination.
INTERPRETATION
Multi-age cohort campaigns had a marked effect on vaccine-type carriage and fractional-dose campaigns met non-inferiority criteria. Such campaigns should be considered in low-coverage settings, including humanitarian emergencies, to accelerate population protection.
Trypanosoma brucei rhodesiense human African trypanosomiasis (r-HAT), the zoonotic, acute form of sleeping sickness in eastern Africa, is lethal if untreated. Today, only one arsenic- based, neurotoxic drug, melarsoprol, is available for treatment of the advanced meningo-encephalitic stage. A new oral treatment would simplify HAT elimination as proposed by WHO. Fexinidazole was recommended by the European Medicines Agency (EMA) in 2018 as the first oral treatment for Trypanosoma brucei gambiense HAT, but it was not yet evaluated for r-HAT.
METHODS
This single-arm clinical trial, sponsored by DNDi, began in October 2019 and tested fexinidazole treatment in patients with r-HAT as an alternative to existing treatment in Malawi and Uganda. Patients (aged ≥6 years) with both stages of the disease were recruited up to the target of 34 patients with stage 2 disease evaluable at the end of hospitalization. Patients were hospitalised during the 10 days of treatment and followed up to 12 months after hospital discharge. The primary outcome was r-HAT-related or treatment-related fatality at the end of hospitalisation in patients with stage 2 disease and was compared with an unacceptable fatality rate of 8.5%, a threshold defined according to results from a previous clinical trial with melarsoprol. This trial is registered with ClinicalTrials.gov, NCT03974178.
RESULTS
45 patients received treatment between 1 October 2019 and 28 November 2021 (35 [78%] had stage 2 disease and ten [22%] stage 1, 31 [69%] were male and 14 [31%] female, with median age of 24 years). The primary efficacy result of the clinical trial, analysed among the 34 evaluable patients, was achieved, with no r-HAT-related or treatment-related deaths during hospitalisation (0.0%, 95% CI 0.0–8.4), compared with a benchmark of 8.5% lethality attributable to melarsoprol. Safety was acceptable, with no severe adverse events related to fexinidazole; and one patient relapsed.
CONCLUSION
Fexinidazole, an oral treatment, was shown to be a good alternative to existing injectable and toxic drugs. Results were submitted for EMA regulatory review in preparation for use in endemic countries, and a positive scientific opinion was received in December 2023 to extend the indication of fexinidazole for the treatment of r-HAT. Fexinidazole is expected to be deployed in 2024 as a new r-HAT therapeutic.
BACKGROUND
After a history of poor treatments for rifampin-resistant tuberculosis (RR-TB), recent advances have resulted in shorter, more effective treatments. However, they are not available to everyone and have shortcomings, requiring additional treatment options.
METHODS
endTB is an international, open-label, Phase 3 non-inferiority, randomized, controlled clinical trial to compare five 9-month all-oral regimens including bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C) and pyrazinamide (Z), to the standard (control) for treatment of fluoroquinolone-susceptible RR-TB. Participants were randomized to 9BLMZ, 9BCLLfxZ, 9BDLLfxZ, 9DCLLfxZ, 9DCMZ and control using Bayesian response-adaptive randomization. The primary outcome was favorable outcome at week 73 defined by two negative sputum culture results or by favorable bacteriologic, clinical and radiologic evolution. The non-inferiority margin was 12 percentage points.
RESULTS
Of 754 randomized patients, 696 and 559 were included in the modified intention to treat (mITT) and per-protocol (PP) analyses, respectively. In mITT, the control had 80.7% favorable outcomes. Regimens 9BCLLfxZ [adjusted risk difference (aRD): 9.5% (95% confidence interval (CI), 0.4 to 18.6)], 9BLMZ [aRD: 8.8% (95%CI, −0.6 to 18.2)], and 9BDLLfxZ [3.9% (95%CI, −5.8 to 13.6)] were non-inferior in mITT and in PP. The proportion of participants experiencing grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxicity occurred in 11.7% of the experimental regimens overall and in 7.1% of the control.
CONCLUSIONS
The endTB trial increases treatment options for RR-TB with three shortened, all-oral regimens that were non-inferior to a current well-performing standard of care.
Treatment for fluoroquinolone-resistant multidrug-resistant/rifampicin-resistant tuberculosis (pre-XDR TB) often lasts longer than treatment for less resistant strains, yields worse efficacy results, and causes substantial toxicity. The newer anti-tuberculosis drugs, bedaquiline and delamanid, and repurposed drugs clofazimine and linezolid, show great promise for combination in shorter, less-toxic, and effective regimens. To date, there has been no randomized, internally and concurrently controlled trial of a shorter, all-oral regimen comprising these newer and repurposed drugs sufficiently powered to produce results for pre-XDR TB patients.
METHODS
endTB-Q is a phase III, multi-country, randomized, controlled, parallel, open-label clinical trial evaluating the efficacy and safety of a treatment strategy for patients with pre-XDR TB. Study participants are randomized 2:1 to experimental or control arms, respectively. The experimental arm contains bedaquiline, linezolid, clofazimine, and delamanid. The control comprises the contemporaneous WHO standard of care for pre-XDR TB. Experimental arm duration is determined by a composite of smear microscopy and chest radiographic imaging at baseline and re-evaluated at 6 months using sputum culture results: participants with less extensive disease receive 6 months and participants with more extensive disease receive 9 months of treatment. Randomization is stratified by country and by participant extent-of-TB-disease phenotype defined according to screening/baseline characteristics. Study participation lasts up to 104 weeks post randomization. The primary objective is to assess whether the efficacy of experimental regimens at 73 weeks is non-inferior to that of the control. A sample size of 324 participants across 2 arms affords at least 80% power to show the non-inferiority, with a one-sided alpha of 0.025 and a non-inferiority margin of 12%, against the control in both modified intention-to-treat and per-protocol populations.
DISCUSSION
This internally controlled study of shortened treatment for pre-XDR TB will provide urgently needed data and evidence for clinical and policy decision-making around the treatment of pre-XDR TB with a four-drug, all-oral, shortened regimen.
A dearth of evidence on abortion complications in fragile settings limits the understanding of women’s needs in access to comprehensive abortion care in contexts like Jigawa state. This study describes the burden of abortion-related complications and their contributing factors in the maternity ward in an MSF-supported referral hospital in Jigawa state, Nigeria. This evidence brief presents selected results for three components of the AMoCo study (Abortion-related Morbidity and Mortality in Conflict-affected and Fragile Settings):
- A quantitative observational study of clinical characteristics of women presenting with any type of abortion complications,
- A quantitative survey with a sub-group of these women who were hospitalized, and
- A qualitative study among selected women with very severe complications (potentially life-threatening and near-miss complications).