Leprosy

This Phase 1 study is designed to assess the safety, tolerability, and pharmacokinetics of single and multiple intravenous doses of BWC0977 when administered to healthy adult volunteers. This is a randomized double-blind, placebo-controlled, ascending dose, multi-cohort trial. A total of 64 healthy volunteers are expected to be enrolled in 8 Cohorts. The study will be conducted in two phases: A single ascending dose (SAD) phase, followed by a multiple ascending dose (MAD) phase. In SAD, participants in Cohorts 1 - 2 will receive one dose of BWC0977 or placebo. In MAD, participants in cohorts 3 - 7 will receive multiple doses of BWC0977 or placebo for 7-10 consecutive days (as per the schedule). In both parts, sequential cohorts will be exposed to increasing doses of BWC0977.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae and is characterized by skin and peripheral nerve involvement. Neural impairment is the main determinant of disability and long-term morbidity. Early diagnosis remains challenging because current diagnostic methods have important limitations. Slit-skin smear microscopy and skin biopsy have low sensitivity in many clinical settings, especially in paucibacillary and primary neural forms. Nerve palpation is widely used but lacks reproducibility and does not distinguish among etiologies of neuropathy. Nerve biopsy, although more precise in selected cases, is invasive and may cause permanent neurological sequelae. High-resolution ultrasonography has emerged as a promising tool for evaluation of leprosy neuropathy because it allows objective assessment of peripheral nerve cross-sectional area, asymmetry, fascicular abnormalities, and intraneural or epineural hypervascularity using Doppler. However, ultrasound cannot directly detect the bacillus. Molecular methods have expanded the diagnostic possibilities in leprosy. Real-time PCR targeting the repetitive element RLEP can detect M. leprae DNA with high sensitivity. However, DNA detection alone does not distinguish viable from non-viable bacilli. Detection of RNA by RT-PCR, including targets such as 16S rRNA and sodA, may provide evidence of bacillary viability because RNA degrades rapidly after cell death. This approach may improve treatment monitoring and refine the concept of cure. The present study proposes a minimally invasive strategy based on ultrasound-guided ulnar perineural subcutaneous aspirate. Biological material will be collected adjacent to the affected nerve, avoiding direct nerve biopsy and potentially increasing the sensitivity of molecular detection in the neural microenvironment. Participants with suspected leprosy will be assessed clinically, by high-resolution ultrasound of the ulnar nerves, and by molecular detection of M. leprae DNA and RNA in aspirated material. They will be evaluated at baseline, near the time of diagnosis, and after one year of treatment. The main objective is to determine the diagnostic accuracy of ultrasound-guided perineural aspirate PCR/RT-PCR compared with conventional methods. Secondary objectives include correlation of ultrasound abnormalities with molecular positivity, assessment of bacillary viability over time, and development of workflows potentially applicable to the public health system, including referral centers and settings using portable ultrasound.

Assuming the phase 2 study will not reveal any drug related adverse events and following the advice of the DSMB and the involved ethics committees, the investigators will proceed with a phase 3 study for which randomization will take place in December, 2022. There will be two study arms. Arm 1 will be the intervention arm in which there will be provided BE-PEP to all persons residing within 100 meters of an index case, to be repeated after four weeks for household contacts. Arm 2 will be the comparator arm in which the WHO recommended standard PEP will be provided, i.e. 10 mg/kg of rifampicin in a single dose. In both arms anyone living within 100 meters of an index case will be targeted or the entire village if more than 50% are eligible. Provision of BE-PEP will start in 2023 and follow-up will continue until 2026. The main study outcome will be the comparison of leprosy risk in individuals that received standard WHO SDR-PEP versus individuals that received BE-PEP. In addition the overall leprosy incidence over the follow-up period will be compared between the two study arms. As stated above, the primary outcome measure will be the incidence rate ratio of leprosy between those who received BE-PEP and those who received the standard SDR-PEP. From this analysis the investigators will exclude those not eligible for BE-PEP, i.e. children below 5 years of age and/or with a weight below 20 kg. A Poisson model will be fit with village nested in island as random effect and controlled for distance to the nearest index case at baseline. In addition the investigators will compute incidence rate ratios between the entire BE-PEP and SDR-PEP arms over the period 2023-2026, also based on a Poisson model with village nested in island as random effect. Throughout the BE-PEOPLE trial the investigators will continue sampling leprosy patients identified (a skin biopsy from the edge of non-facial lesions), with the aim of using molecular assays for M. leprae as quality assurance mechanism. If sufficient DNA is available Deeplex-MycLep will be used for typing the strains, which will allow to perform highly sensitive surveillance for (traces of) resistance to rifampicin and bedaquiline. As part of BE-PEOPLE, the investigators will moreover enroll all microbiologically confirmed tuberculosis patients on all islands of Comoros (Moheli, Anjouan, and Grande Comore, where bedaquiline will not be introduced, maximum 100 patients/ year) and assess whether they ever received (BE-)PEP or leprosy treatment. The investigators will genotype their sputum with Deeplex-MycTB XL, which includes all M. tuberculosis genes (potentially) involved in resistance to rifampicin and bedaquiline, to be able to detect the earliest traces of acquired resistance to these drugs, which is unexpected after single dose administration.The overall goal of BE-PEOPLE is to validate a robust and safe leprosy PEP regimen, and its optimal administration, that prevents leprosy in the individual and interrupts transmission at the village level.If BE-PEP turns out to be safe and successful, the investigators aim to adjust national guidelines in Comoros towards island wide implementation on Anjouan and Moheli, allowing to sustainably eliminate leprosy.

A double-blind, placebo-controlled randomized proof-of-concept Phase 2 trial will be performed evaluating the efficacy, safety and tolerability of adjunct metformin combined with standard of care MDT to mitigate leprosy reactions. Patients with newly diagnosed multibacillary leprosy will be randomized (1:1) to metformin 1000mg OD versus placebo for 24 weeks in addition to MDT during 48 weeks. The trial aims to enroll 166 patients, aged between 18-65 years old, in leprosy endemic areas in Indonesia. Primary endpoints are the proportion of participants experiencing a leprosy reaction during the full duration of the study and the proportion of participants with at least one adverse event within the first 28 weeks of the study. Secondary endpoints are the severity and time to first leprosy reaction, the number of leprosy reactions, the cumulative corticosteroid usage, and quality of life. The total study follow-up is 48 weeks. This METLEP trial is financially supported by the Leprosy Research Initiative (grant number: FP20\\4).

This study will be conducted as a nested sub-study within a main longitudinal study implemented online. The baseline assessment of the longitudinal study was conducted between October and November 2025. Participants who agreed to be recontacted will be invited to join the randomized controlled trial (RCT) approximately four months after the baseline assessment, in February-March 2026. At that time, participants will be randomized in a 1:1 ratio into either the intervention or control group.

The major role of human genetic factors in the immune response to infections is now well established, particularly for viral infections. In the context of the COVID-19 pandemic, the following results have identified 1) several inborn errors of immunity (IEI) affecting the response or production of type I interferons (type I IFNs) in around 4% of adult patients with severe clinical disease, and 2) the presence of type I IFN-neutralizing autoantibodies (auto-Abs) in around 15% of severe cases, and 20% of deaths. The investigators would like to carry out a longitudinal immunological and clinical follow-up study on a prospective cohort of patients with either a genetic defect affecting the type I IFN-dependent immune response, or anti-IFN-I auto-Abs, to monitor the incidence of infectious and/or autoimmune events in these individuals, the evolution of neutralizing power, and the kinetics of auto-Abs. This should lead to a better understanding of the prevention and management of these patients. The research design is a national multicenter prospective cohort of adults with 1) anti-IFN-I auto-Abs or 2) IEI- IFN-I, with follow-up from 1 to 4 years. These individuals may be: 1) patients who have or have had clinical disease (related to COVID-19, other viral infections, autoimmune disorders); or 2) "healthy" participants (e.g. blood donors, relatives of an IEI patient). Follow-up will include: * yearly visits to the Clinical Investigation Center (CIC) or a clinical department with blood sampling; * specific visit in case of hospitalization for infectious events or adverse effects of vaccination, exacerbation or new diagnosis of auto-immune disease, new diagnosis of cancer, or SARS-CoV-2 infection whether or not patients are admitted to hospital, with blood sampling. In addition, a retrospective "passive" follow-up will be implemented through matching with the data from the SNDS (National Health Data System), in order to collect clinical events of and healthcare resource consumption. Moreover, matching with controls adults from the national CONSTANCES cohort, not carrying auto-Abs against type I IFNs nor IEI-IFN-I, will be performed. (ratio 3:1; matching on age (+/- 5 years), gender and geographic region of recruitment). Individuals under long-lasting immunosuppressive or immunomodulatory drugs will not be eligible. Follow-up of controls, which will be carried out as part of the CONSTANCES cohort, will include web-based questionnaires, every 12 months, in addition to linking with SNDS data as already done in this cohort. Inclusion visit: After signing the consent form, the following tests will be performed: * Demographic characteristics (sex, age, country of birth) * Medical history from participant and family member(s) including infectious and auto-immune diseases, cancers and vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigations (anti-nuclear, anti-ENA, native anti-DNA, anti- thyroid antibodies, rheumatoid factor); * immunophenotyping\*; * auto-Abs against type I IFNs, other cytokines\*, or other target proteins\* (dosage and neutralization activity); * Genetic explorations by whole-exome or whole-genome sequencing\*; * Biobanking (DNA, plasma/sera; cryopreserved peripheral blood mononuclear cells (PBMCs). * these biological analyses will be carried out as part of dedicated COVIFERON RHU5 workpackages. In addition, vaccination against SARS-CoV-2 and influenza will be offered to these subjects as a priority, as part of their usual care. Follow-up visits : Annual visits to the CIC : * Medical history since last visit, including infectious, auto-immune and oncologic events, vaccination status and side effects * Blood samples for: * full blood cell count; * classical autoimmune investigation (anti-nuclear, anti-ENA, native anti- DNA, anti-thyroid antibodies, rheumatoid factor); * immunophenotyping; * Auto-Abs against type I IFNs, other cytokines, or other target proteins (dosage and neutralization) * Biobanking (DNA, plasma, cryopreserved peripheral blood mononuclear cells (PBMCs)) Additional specific visit in the event of a clinical event of interest, at any time during follow-up: * In case of SARS-CoV-2 infection, whatever the severity of the disease: blood sampling for determination and neutralization of type I anti-IFN autoAbs, CBC, and biobanking (plasma and PBMC) and teleconsultation with the CIC in charge of patients, as soon as possible. * In the event of hospitalization for infectious events or exacerbation or new diagnosis of an auto-immune disease: blood sampling for determination and neutralization of anti-IFN-I autoAbs, CBC, and biobanking (plasma and PBMCs) and collection of the hospitalization report in the case report form on a dedicated page.

The goal of this clinical trial is to assess whether a multifactorial active case-finding strategy improves the detection of leprosy cases in Brazil compared to usual screening practices. The main questions it aims to answer are: \- Does the intervention increase the number of new leprosy cases detected compared to standard care? Participants will: * Receive community awareness about leprosy. * Be screened using the Leprosy Suspicion Questionnaire at priority areas identified by georeference tools. * Undergo clinical evaluation by a trained medical team. * If leprosy is diagnosed, affected patients will collect complementary laboratory exams Healthcare professionals from primary care units will receive training in leprosy, while researchers will monitor changes in leprosy incidence over a 12-month period using data from Brazil's national notification system. The study will provide insights into underdiagnosis and the clinical profiles of patients who have been diagnosed.

A stable leprosy new case detection rate in many endemic countries indicates that the transmission of M. leprae is continuing unabated and that the current control strategy of case finding and provision of multi drug therapy (MDT) is not sufficient. Immunoprophylaxis by vaccination or post-exposure prophylaxis (PEP) with antibiotics provide effective strategies for the prevention of leprosy. Prophylactic treatment with single dose rifampicin (SDR) has shown to be a successful method to prevent leprosy in contacts of newly diagnosed leprosy patients (1). Currently, the Leprosy Post-Exposure Prophylaxis (LPEP) program generates evidence on the feasibility of integrating contact tracing and single-dose rifampicin (SDR) administration into routine leprosy control activities within the national leprosy control programmes of Brazil, Cambodia, India, Indonesia, Myanmar, Nepal, Sri Lanka and Tanzania \[Steinmann P, et al\]. Recently, the world health orginazation (WHO) has endorsed PEP for routine application in their new "Guidelines for the diagnosis, treatment and prevention of leprosy". Genomic and transcriptomics analysis (e.g. population- and twin studies \[5\]), have determined that the host genetic background is an important risk factor for leprosy susceptibility. In addition, close contacts of leprosy patients have a higher risk of developing the disease (2, 3), which therefore represents the primary target group for interventions (4). To target individuals spreading leprosy bacilli for prophylactic treatment, M. leprae infection needs to be measurable objectively. Antibody levels correspond with bacterial load and risk of transmission. Also, individuals seropositive for anti-M. leprae phenolic glycolipid-I (PGL-I) antibodies, are at 5-8 fold higher risk of leprosy (5, 6). Moreover, in a leprosy endemic area in Bangladesh, we recently showed significant added value of cellular markers (cytokines, chemokines, acute phase proteins) to identify infection (7). Thus, for implementation in a PEP-approach, new tests that indicate who needs treatment should allow detection of both cellular-and humoral markers. In previous studies applying UCP-LFA in 4 countries with variable leprosy endemicity (Bangladesh, Brazil, China and Ethiopia), we have shown that the combined assessment of serum levels of multiple biomarkers including anti-PGL-I Ab as well as cytokines, significantly improved the diagnostic potential for detection of M. leprae infected individuals. This demonstrates that UCP-LFAs for detection of multiple biomarkers can provide valuable tools for more accurate detection of M. leprae infection. Its low-complexity POC format and applicability for use of finger-stick blood allows large scale screening efforts in field settings. Moreover, the format of the UCP-LFA is being further developed in various other projects (focused on tuberculosis and leprosy diagnostic tests). This has recently resulted in a multi-biomarker test (MBT) format that allows simultaneous detection of up to 6 markers, which is currently further evaluated in the field for tuberculosis diagnostic purposes. Since the UCP-LFA format is flexible and can accommodate for detection of different markers, this latest development will also enable combined detection of humoral and cellular biomarkers which together represent a specific signature for M. leprae infection.

PENGUIN is a pragmatic, blinded (outcome assessor), 2x2 factorial, multi-centre randomised controlled trial, with an internal pilot, to evaluate measures to reduce surgical site infection (SSI) and pneumonia rates in patients undergoing surgery with an abdominal incision. Pneumonia is one of the most serious complications to occur after surgery, accounting for up to one in four of all postoperative deaths. The incidence is greater still in high-risk populations such as those undergoing midline laparotomy where mortality rates are more than 10%. SSIs are clearly important being the most frequent healthcare-associated infection in LMICs, affecting one in three patients undergoing contaminated or dirty surgery (34, 35). SSIs cause pain, discomfort and disability. They increase the time taken to return to work, and healthcare costs The risk of postoperative mortality and complications such as surgical site infection is three times greater in low and middle-income countries (LMICs) than in high-income countries. In order to address surgical need worldwide, it is estimated that provision of a further 312 million operations would be required each year. Patients will be recruited from hospitals in Low and Middle Income Countries (LMICs) who are undergoing elective or emergency mid-line laparotomy. Eligible patients will be randomised at the level of the individual in a 1:1:1:1 ratio between: A. Preoperative chlorhexidine mouthwash and 80-100% FiO2 during surgery B. No preoperative chlorhexidine mouthwash and 80-100% FiO2 during surgery C. Preoperative chlorhexidine mouthwash and 21-30% FiO2 during surgery D. No preoperative chlorhexidine mouthwash and 21-30% FiO2 during surgery The 6 month internal pilot will assess the feasibility of recruitment, compliance with treatment allocation and patient retention and follow-up rates. The main Randomised Control Trial will recruit 12,924 participants.

Inappropriate antibiotic prescribing in primary care contributes to the development of antimicrobial resistance. Despite guidelines and public health efforts, overprescribing remains prevalent, especially for self-limiting infections which often resolve without antibiotic treatment. Digital tools such as a Prescription Search Support (PSS) may aid general practitioners (GPs) in making more informed prescribing decisions. This implementation project builds upon a previously conducted mixed-methods implementation study evaluating the usability of a PSS, which was approved by the Ethical Review Board UZ KU Leuven (Onderwijs-Begeleidingscommissie) on 27 September 2024 (MP031770). The PSS under study contains the current recommendations for the proper use of antimicrobial agents for common infections in ambulatory care in Belgium. In other words, it represents the BAPCOC guidelines in a digital and user-friendly environment, by using a decision tree. Advice for the following diagnoses (ICPC-2 codes) is included in the PSS: sore throat (R21, R74), pertussis (R71), common cold (R74), acute rhinosinusitis (R75), acute bronchitis / bronchiolitis (R78), influenza (R80), pneumonia (R81), ear pain (H01), otorrhea (H04), acute otitis media (H71), acute epiglottitis (R77), acute exacerbations of chronic obstructive pulmonary disease, aspiration pneumonia (R81), laryngitis stridulosa (R77), acute cystitis (U71), acute prostatitis (Y73), acute pyelonephritis (U70), acute vulvovaginitis (X84), asymptomatic bacteriuria, epididymo-orchitis (Y74), genital herpes (Y72, X90), partner treatment and treatment of asymptomatic sexually transmitted infections, pelvic inflammatory disease (X74), syphilis (X70, Y70), and urethritis (U72). This PSS was developed as part of the Belgian National Action Plan on AMR by the Federal Public Service Health, Food Chain Safety and Environment and the National Institute for Health and Disability Insurance (NIHDI; RIZIV-INAMI), in collaboration with various experts and stakeholders, including physicians, infectiologists, hygienists, policymakers, guideline developers, and software developers. The company Smals, under instruction of RIZIV-INAMI, developed the software for this application in close collaboration with the RIZIV-INAMI working group. Guideline recommendations regarding appropriate prescribing of antimicrobials in ambulatory care were converted into decision rules, which serve as the knowledge source for the PSS. Digital education offers several advantages, such as easy access without time or location constraints, varying possible forms and levels, and the ability to disseminate evidence on a large scale. Previous research has shown that standalone web- or smartphone-based applications in this context have the potential to increase physicians' knowledge of antimicrobials and guideline recommendations, potentially improving guideline adherence. In Belgium, antibiotic use in ambulatory care is closely monitored through the Antibiotic Barometer, a national surveillance system coordinated by the Academic Centre of General Practice of KU Leuven and financed by the National Institute for Health and Disability Insurance (RIZIV-INAMI). The Antibiotic Barometer was approved by the Sociaal-maatschappelijke Ethische Commissie (SMEC; G-2023-6352) and provides quarterly feedback to general practices based on routine health insurance claims data. This study evaluates the implementation and impact of the PSS in routine Belgian primary care using a stepped-wedge cluster randomized trial design. Participating general practices are recruited to ensure broad representation across Belgian primary care. General practices constitute the unit of randomization and are randomly allocated to one of four predefined implementation steps. All practices start in a control condition without access to the PSS and transition once to the intervention condition according to their assigned step. Each implementation step lasts three months, after which practices retain access to the PSS for the remainder of the study period. By the end of the study, all participating practices will have received access to the intervention. Data for this study are derived from routine sources and handled within the secure data infrastructure of KU Leuven. Prescribing data obtained via the Antibiotic Barometer are aggregated and pseudonymized at practice level prior to analysis, ensuring that individual patients cannot be identified. Data linkage, storage, and analysis are conducted in accordance with applicable data protection regulations. Quantitative and qualitative analyses are used to evaluate both the effectiveness and implementation of the PSS in real-world primary care. Findings from this study will inform future policy decisions regarding national rollout, optimization, and long-term integration of the PSS within Belgian antimicrobial stewardship strategies.