The importance of appropriate selection of clinical endpoints in outpatient COVID-19 clinical trials.

Clinical trial endpoints must be carefully and intentionally selected so that the results of the trial can be used to inform policy- and decision-making. The relative importance of potential endpoints often depends on the stakeholder, with patients having different preferences to policymakers and regulators. The set up of clinical trials for COVID-19 was problematic, as endpoints that could be reasonably measured did not always match the efficacy endpoints usually required by guideline panels. Thus, different endpoints were used, which made the timely comparison and evaluation of interventions difficult. Here we discuss the evolution of the COVID-19 landscape and the effect this is having on the selection of consistent and measurable clinical trial endpoints. Using appropriate endpoints is crucial for researchers to offer the most reliable, valid, and interpretable results possible.

Vaccines and therapeutics for immunocompromised patients with COVID-19.

The COVID-19 pandemic has disproportionately impacted immunocompromised patients. This diverse group is at increased risk for impaired vaccine responses, progression to severe disease, prolonged hospitalizations and deaths. At particular risk are people with deficiencies in lymphocyte number or function such as transplant recipients and those with hematologic malignancies. Such patients' immune responses to vaccination and infection are frequently impaired leaving them more vulnerable to prolonged high viral loads and severe complications of COVID-19. Those in turn, have implications for disease progression and persistence, development of immune escape variants and transmission of infection. Data to guide vaccination and treatment approaches in immunocompromised people are generally lacking and extrapolated from other populations. The large clinical trials leading to authorisation and approval of SARS-CoV-2 vaccines and therapeutics included very few immunocompromised participants. While experience is accumulating, studies focused on the special circumstances of immunocompromised patients are needed to inform prevention and treatment approaches.

Determination of the Optimal Single Dose Treatment for Acoziborole, a Novel Drug for the Treatment of Human African Trypanosomiasis: First-in-Human Study.

BACKGROUND AND OBJECTIVES: Acoziborole is a novel boron-containing candidate developed as an oral drug for the treatment of human African trypanosomiasis (HAT). Results from preclinical studies allowed progression to Phase 1 trials. We aimed to determine the best dose regimen for all stages of HAT. METHODS: Acoziborole was assessed in 128 healthy adult males of sub-Saharan African origin living in France. The study included a single oral administration of a 20- to 1200-mg dose in a randomised double-blind study in cohorts of 8 (6 active, 2 placebo) to assess safety, tolerability, and pharmacokinetics. In three additional open cohorts of 6 participants, the effect of activated charcoal was evaluated, bioequivalence of capsules versus tablets was assessed, and safety in the 960-mg tablet cohorts was monitored. RESULTS: Acoziborole was well tolerated at all doses tested; no dose-related adverse events were observed. The drug appeared rapidly in plasma (at 1 h), reached tmax between 24 and 72 h, and remained stable for up to 96 h, after which a slow decrease was quantifiable until 14 weeks after dosing. Charcoal had little impact on the enterohepatic recirculation effect, except for the 20-mg dose. Bioequivalence between capsule and tablet formulations was demonstrated. The therapeutic single dose for administration under fasted conditions was fixed to 960 mg. The maximum administered dose was 1200 mg. CONCLUSIONS: This study showed that acoziborole could be safely assessed in patients as a potential single-dose oral cure for both stages of gambiense HAT. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov: NCT01533961.

Efficacy and safety of acoziborole in patients with human African trypanosomiasis caused by Trypanosoma brucei gambiense: a multicentre, open-label, single-arm, phase 2/3 trial.

BACKGROUND: Human African trypanosomiasis caused by Trypanosoma brucei gambiense (gambiense HAT) in patients with late-stage disease requires hospital admission to receive nifurtimox-eflornithine combination therapy (NECT). Fexinidazole, the latest treatment that has been recommended by WHO, also requires systematic admission to hospital, which is problematic in areas with few health-care resources. We aim to assess the safety and efficacy of acoziborole in adult and adolescent patients with gambiense HAT. METHODS: This multicentre, prospective, open-label, single-arm, phase 2/3 study recruited patients aged 15 years or older with confirmed gambiense HAT infection from ten hospitals in the Democratic Republic of the Congo and Guinea. Inclusion criteria included a Karnofsky score greater than 50, ability to swallow tablets, a permanent address or traceability, ability to comply with follow-up visits and study requirements, and agreement to hospital admission during treatment. Oral acoziborole was administered as a single 960 mg dose (3 × 320 mg tablets) to fasted patients. Patients were observed in hospital until day 15 after treatment administration then for 18 months as outpatients with visits at 3, 6, 12, and 18 months. The primary efficacy endpoint was the success rate of acoziborole treatment at 18 months in patients with late-stage gambiense HAT (modified intention-to-treat [mITT] population), based on modified WHO criteria. A complementary post-hoc analysis comparing the 18-month success rates for acoziborole and NECT (using historical data) was performed. This study is registered at ClinicalTrials.gov, NCT03087955. FINDINGS: Between Oct 11, 2016, and March 25, 2019, 260 patients were screened, of whom 52 were ineligible and 208 were enrolled (167 with late-stage and 41 with early-stage or intermediate-stage gambiense HAT; primary efficacy analysis set). All 41 (100%) patients with early-stage or intermediate-stage and 160 (96%) of 167 with late-stage disease completed the last 18-month follow-up visit. The mean age of participants was 34·0 years (SD 12·4), including 117 (56%) men and 91 (44%) women. Treatment success rate at 18 months was 95·2% (95% CI 91·2-97·7) reached in 159 of 167 patients with late-stage gambiense HAT (mITT population) and 98·1% (95·1-99·5) reached in 159 of 162 patients (evaluable population). Overall, 155 (75%) of 208 patients had 600 treatment-emergent adverse events. A total of 38 drug-related treatment-emergent adverse events occurred in 29 (14%) patients; all were mild or moderate and most common were pyrexia and asthenia. Four deaths occurred during the study; none were considered treatment related. The post-hoc analysis showed similar results to the estimated historical success rate for NECT of 94%. INTERPRETATION: Given the high efficacy and favourable safety profile, acoziborole holds promise in the efforts to reach the WHO goal of interrupting HAT transmission by 2030. FUNDING: Bill & Melinda Gates Foundation, UK Aid, Federal Ministry of Education and Research, Swiss Agency for Development and Cooperation, Médecins Sans Frontières, Dutch Ministry of Foreign Affairs, Norwegian Agency for Development Cooperation, Norwegian Ministry of Foreign Affairs, the Stavros Niarchos Foundation, Spanish Agency for International Development Cooperation, and the Banco Bilbao Vizcaya Argentaria Foundation. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease.

BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months. RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days. CLINICAL TRIALS REGISTRATION: NCT02498782.

Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model.

The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.

Antidepressant Use and Its Association with 28-Day Mortality in Inpatients with SARS-CoV-2: Support for the FIASMA Model against COVID-19.

To reduce Coronavirus Disease 2019 (COVID-19)-related mortality and morbidity, widely available oral COVID-19 treatments are urgently needed. Certain antidepressants, such as fluvoxamine or fluoxetine, may be beneficial against COVID-19. We included 388,945 adult inpatients who tested positive for SARS-CoV-2 at 36 AP−HP (Assistance Publique−Hôpitaux de Paris) hospitals from 2 May 2020 to 2 November 2021. We compared the prevalence of antidepressant use at admission in a 1:1 ratio matched analytic sample with and without COVID-19 (N = 82,586), and assessed its association with 28-day all-cause mortality in a 1:1 ratio matched analytic sample of COVID-19 inpatients with and without antidepressant use at admission (N = 1482). Antidepressant use was significantly less prevalent in inpatients with COVID-19 than in a matched control group of inpatients without COVID-19 (1.9% versus 4.8%; Odds Ratio (OR) = 0.38; 95%CI = 0.35−0.41, p < 0.001). Antidepressant use was significantly associated with reduced 28-day mortality among COVID-19 inpatients (12.8% versus 21.2%; OR = 0.55; 95%CI = 0.41−0.72, p < 0.001), particularly at daily doses of at least 40 mg fluoxetine equivalents. Antidepressants with high FIASMA (Functional Inhibitors of Acid Sphingomyelinase) activity seem to drive both associations. These treatments may reduce SARS-CoV-2 infections and COVID-19-related mortality in inpatients, and may be appropriate for prophylaxis and/or COVID-19 therapy for outpatients or inpatients.

Safety and efficacy of oral fexinidazole in children with gambiense human African trypanosomiasis: a multicentre, single-arm, open-label, phase 2-3 trial.

BACKGROUND: Fexinidazole has been reported as an effective oral monotherapy against non-severe gambiense human African trypanosomiasis in a recent trial in adults. We aimed to assess the safety and efficacy of fexinidazole in children across all disease stages of gambiense human African trypanosomiasis. METHODS: We did a multicentre, single-arm, open-label, phase 2-3 trial at eight district hospitals in the Democratic Republic of the Congo. We recruited children with a Karnofsky score of more than 50, those aged 6 years to younger than 15 years, weighing 20 kg or more, and with confirmed gambiense human African trypanosomiasis (any stage). Children weighing 20 kg or more and less than 35 kg received oral fexinidazole of 1200 mg (two × 600 mg tablets) once per day for 4 days (days 1-4) followed by 600 mg (one × 600 mg tablet) once per day for 6 days (days 5-10). Children weighing 35 kg or more received oral fexinidazole of 1800 mg (three × 600 mg tablets) once per day for 4 days (days 1-4), followed by 1200 mg (two × 600 mg tablets) once per day for 6 days (days 5-10). The primary endpoint was fexinidazole treatment success rate 12 months after end of treatment. A rate greater than 80% was deemed acceptable and a target value of 92% was aimed for. Safety was assessed through routine monitoring. This study is completed and registered with ClinicalTrials.gov, number NCT02184689. FINDINGS: Between May 3, 2014, and Nov 22, 2016, we screened a total of 130 paediatric patients, of whom 125 (96%) received at least one dose of fexinidazole. All 125 patients (69 [55%] patients with stage 1, 19 [15%] with early stage 2, and 37 [30%] with late stage 2 gambiense human African trypanosomiasis) completed the 10-day treatment. Treatment success rate at 12 months was 97·6% (95% CI 93·1-99·5; 122 of 125 patients). The primary endpoint was met and the targeted value of 92% was exceeded. Treatment success at 12 months was elevated across all disease stages: 98·6% (95% CI 92·2-99·9; 68 of 69 patients) in stage 1, 94·7% (74·0-99·9; 18 of 19 patients) in early stage 2, and 97·3% (85·8-99·9; 36 of 37 patients) in late stage 2 gambiense human African trypanosomiasis. No new safety issues were observed beyond those found in adult trials. Overall, 116 (93%) of 125 patients reported 586 treatment-emergent adverse events, mainly mild or moderate. The most frequently reported treatment-emergent adverse events of interest during hospital admission were vomiting (86 [69%] of 125) and headache (41 [33%]). Seven (6%) of 125 patients had severe malaria, which was often accompanied by anaemia that was unrelated to fexinidazole. One patient died following dyspnoea and injury due to traumatic aggression 172 days after end of treatment, which was considered unrelated to fexinidazole or gambiense human African trypanosomiasis. INTERPRETATION: Oral fexinidazole is a safe and effective first-line treatment option across all gambiense human African trypanosomiasis disease stages in paediatric patients. FUNDING: Through the Drugs for Neglected Diseases initiative: the Bill & Melinda Gates Foundation (USA), the Republic and Canton of Geneva (Switzerland), the Dutch Ministry of Foreign Affairs (Netherlands), the Norwegian Agency for Development Cooperation (Norway), the Federal Ministry of Education and Research through KfW (Germany), the Brian Mercer Charitable Trust (UK), and other private foundations and individuals from the human African trypanosomiasis campaign. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Development and Introduction of Fexinidazole into the Global Human African Trypanosomiasis Program.

In this article, the authors show the strategy used to streamline the introduction of fexinidazole, the first all oral treatment of human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense. The dose range was determined in phase 1 studies and a significant food effect was observed, which was tested with field-adapted meals. The pharmacokinetic profile required definition of a higher loading dosage for the first 4 days and administration of the daily dose together with a typical local meal to optimize product absorption and rapidly achieve drug steady state. This allowed for a combined phase II/III pivotal study directly after phase I trials. Partnerships with highly engaged actors from endemic country control programs and international research institutions started early through the HAT platform, building on an agreed target product profile (TPP), establishing a regulatory plan early and transparently including endemic countries in the research and data flow. A key element that enabled a quick start to access activities was preparing for World Health Organization guidelines early and starting the process prior to registration. Distribution plans were identified and supply was established from the start, by taking advantage of the existing supply agreement between the producers of all HAT drugs (Sanofi and Bayer) and the WHO. Pharmacovigilance and phase 4 studies were nested into wider implementation activities. Targeted sequential introduction into national programs was prioritized, based on medical need and epidemiologically updated information.

Definitions matter: Heterogeneity of COVID-19 disease severity criteria and incomplete reporting compromise meta-analysis.

Therapeutic efficacy in COVID-19 is dependent upon disease severity (treatment effect heterogeneity). Unfortunately, definitions of severity vary widely. This compromises the meta-analysis of randomised controlled trials (RCTs) and the therapeutic guidelines derived from them. The World Health Organisation 'living' guidelines for the treatment of COVID-19 are based on a network meta-analysis (NMA) of published RCTs. We reviewed the 81 studies included in the WHO COVID-19 living NMA and compared their severity classifications with the severity classifications employed by the international COVID-NMA initiative. The two were concordant in only 35% (24/68) of trials. Of the RCTs evaluated, 69% (55/77) were considered by the WHO group to include patients with a range of severities (12 mild-moderate; 3 mild-severe; 18 mild-critical; 5 moderate-severe; 8 moderate-critical; 10 severe-critical), but the distribution of disease severities within these groups usually could not be determined, and data on the duration of illness and/or oxygen saturation values were often missing. Where severity classifications were clear there was substantial overlap in mortality across trials in different severity strata. This imprecision in severity assessment compromises the validity of some therapeutic recommendations; notably extrapolation of "lack of therapeutic benefit" shown in hospitalised severely ill patients on respiratory support to ambulant mildly ill patients is not warranted. Both harmonised unambiguous definitions of severity and individual patient data (IPD) meta-analyses are needed to guide and improve therapeutic recommendations in COVID-19. Achieving this goal will require improved coordination of the main stakeholders developing treatment guidelines and medicine regulatory agencies. Open science, including prompt data sharing, should become the standard to allow IPD meta-analyses.

Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed.

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.

Global public health security and justice for vaccines and therapeutics in the COVID-19 pandemic.

A Lancet Commission for COVID-19 task force is shaping recommendations to achieve vaccine and therapeutics access, justice, and equity. This includes ensuring safety and effectiveness harmonized through robust systems of global pharmacovigilance and surveillance. Global production requires expanding support for development, manufacture, testing, and distribution of vaccines and therapeutics to low- and middle-income countries (LMICs). Global intellectual property rules must not stand in the way of research, production, technology transfer, or equitable access to essential health tools, and in context of pandemics to achieve increased manufacturing without discouraging innovation. Global governance around product quality requires channelling widely distributed vaccines through WHO prequalification (PQ)/emergency use listing (EUL) mechanisms and greater use of national regulatory authorities. A World Health Assembly (WHA) resolution would facilitate improvements and consistency in quality control and assurances. Global health systems require implementing steps to strengthen national systems for controlling COVID-19 and for influenza vaccinations for adults including pregnant and lactating women. A collaborative research network should strive to establish open access databases for bioinformatic analyses, together with programs directed at human capacity utilization and strengthening. Combating anti-science recognizes the urgency for countermeasures to address a global-wide disinformation movement dominating the internet and infiltrating parliaments and local governments.

The Chagas disease study landscape: A systematic review of clinical and observational antiparasitic treatment studies to assess the potential for establishing an individual participant-level data platform.

BACKGROUND: Chagas disease (CD), caused by the parasite Trypanosoma cruzi, affects ~6-7 million people worldwide. Significant limitations still exist in our understanding of CD. Harnessing individual participant data (IPD) from studies could support more in-depth analyses to address the many outstanding research questions. This systematic review aims to describe the characteristics and treatment practices of clinical studies in CD and assess the breadth and availability of research data for the potential establishment of a data-sharing platform. METHODOLOGY/PRINCIPAL FINDINGS: This review includes prospective CD clinical studies published after 1997 with patients receiving a trypanocidal treatment. The following electronic databases and clinical trial registry platforms were searched: Cochrane Library, PubMed, Embase, LILACS, Scielo, Clintrials.gov, and WHO ICTRP. Of the 11,966 unique citations screened, 109 (0.9%) studies (31 observational and 78 interventional) representing 23,116 patients were included. Diagnosis for patient enrolment required 1 positive test result in 5 (4.6%) studies (2 used molecular method, 1 used molecular and serology, 2 used serology and parasitological methods), 2 in 60 (55.0%), 3 in 14 (12.8%) and 4 or more in 4 (3.7%) studies. A description of treatment regimen was available for 19,199 (83.1%) patients, of whom 14,605 (76.1%) received an active treatment and 4,594 (23.9%) were assigned to a placebo/no-treatment. Of the 14,605 patients who received an active treatment, benznidazole was administered in 12,467 (85.4%), nifurtimox in 825 (5.6%), itraconazole in 284 (1.9%), allopurinol in 251 (1.7%) and other drugs in 286 (1.9%). Assessment of efficacy varied largely and was based primarily on biological outcome; parasitological efficacy relied on serology in 67/85 (78.8%) studies, molecular methods in 52/85 (61.2%), parasitological in 34/85 (40.0%), microscopy in 3/85 (3.5%) and immunohistochemistry in 1/85 (1.2%). The median time at which parasitological assessment was carried out was 79 days [interquartile range (IQR): 30-180] for the first assessment, 180 days [IQR: 60-500] for second, and 270 days [IQR: 18-545] for the third assessment. CONCLUSIONS/SIGNIFICANCE: This review demonstrates the heterogeneity of clinical practice in CD treatment and in the conduct of clinical studies. The sheer volume of potential IPD identified demonstrates the potential for development of an IPD platform for CD and that such efforts would enable in-depth analyses to optimise the limited pharmacopoeia of CD and inform prospective data collection.