Parasitic Infection

Onchocerciasis and loiasis are parasitic diseases caused by Onchocerca volvulus and Loa loa, respectively. Onchocerciasis is endemic in 31 African countries, parts of South America, and Yemen, affecting around 37 million people, while loiasis is present in Central Africa, infecting approximately 15 million individuals. Both diseases are associated with severe complications and increased mortality. African countries have implemented mass drug administration (MDA) programs using ivermectin to combat onchocerciasis. However, co-endemic loiasis poses challenges due to the risk of severe adverse events. Current strategies involve alternative treatments and chemoprophylaxis to accelerate onchocerciasis elimination. The project aims to evaluate the use of levamisole as an alternative treatment. This project will assess the safety and efficacy of administering levamisole for 3 and 5 days to reduce Loa microfilarial density. Previous research demonstrated the safety of a single dose of levamisole but indicated the need for longer treatment regimens to achieve a significant reduction in Loa microfilarial density. The project aims to test whether 3- and 5-day levamisole regimens induce an acceptable safety profile and a stronger reduction in Loa microfilarial density.

This study is a blood-stage P. vivax human challenge study with the primary aim of assessing the safety and feasibility of a challenge model using banks of cryopreserved P. vivax infected erythrocytes produced from NCT04083508 study to identify the dose of the inocula to be used in the future CHMI studies. Forty-eight healthy Thai adults, aged between 20 and 55 years will be recruited at the Clinical Therapeutics Unit (CTU) in the Hospital for Tropical Diseases, Faculty of Tropical Medicine, Mahidol University, Bangkok. The overall period of each volunteer's participation will be 13 months: 2-week screening process prior to the Day 0 challenge, about 2-week inoculum process until reaching malarial treatment criteria, and follow-up period for 1 year after malarial treatment. All inclusion and exclusion criteria will be checked to ensure eligibility criteria have been met prior to Day 0. Volunteers will be admitted to the hospital one day prior to challenged day. All eligible volunteers will have physical examinations. Serum pregnancy test (women only), malaria diagnosis, complete blood count (CBC), and biochemistry will be tested. Glucose -6-phospate dehydrogenase (G6PD) test and malaria immunological profiles will be tested for baseline information. On the challenged day (Day 0), four different doses of inoculum (one whole vial,1:5 dilution, 1:10 dilution, and 1:20 dilution) will be assessed. Each dose of inoculum will be tested in 2 volunteers to identify the lowest concentration producing a reliable infection within a practicable timeframe. Therefore, there will be 8 volunteers enrolled per inoculum bank. The assessment will be repeated in each inoculum bank. There are currently 4 inoculum banks and 20 volunteers have been enrolled to date so 28 volunteers will be enrolled into this study. From Day 1 after challenge, the volunteers will be assessed once daily until malaria qPCR becomes positive. The assessment includes a clinical well-being check, physical examination, vital signs, and blood drawn for parasitaemia (malaria blood film, qPCR, and gametocyte qPCR) and membrane feeding to assess the transmissibility of gametocyte. Malaria immunology and CBC will be performed on day 4 and the day that qPCR become positive. After qPCR becomes positive the monitoring of clinical well-being will continue. Blood will be drawn twice daily to monitor blood parasitaemia and allow membrane feeding to assess the transmissibility of gametocyte. Malaria immunology, CBC, and blood biochemistry will be performed on day that volunteer reach malaria treatment criteria. When the malaria slide positivity and/or symptoms thresholds have been reached study physician will immediately prescribe antimalarial treatment with chloroquine according to local standard guidelines. Blood will be collected to test for malaria (blood films and qPCR) once daily until clinically recovered and two consecutive malaria blood films are negative (completing of the chloroquine treatment course) and volunteers will be discharged from the hospital. Before discharge from the hospital, HIV-I and HIV-II antigen, HBV and HCV serology, COVID-19 testing (RT-PCR) and COVID-19 serology test will be carried out to confirm that volunteers did not acquire COVID-19 during their inpatient stay. If any volunteer reaches day 21 post-challenge without a positive malaria blood film, they shall be started on 3-day course of antimalarial treatment (chloroquine). If a volunteer withdraws/is withdrawn from the study after challenge but before reaching the criteria for malaria treatment, then a complete, appropriate, curative course of antimalarial therapy must be completed After discharge from the hospital, there will be out-patient visits on day 7, 28, 60, 90, 180, and 1 year post antimalarial treatment initiation. Blood will be collected to detect malaria parasites by blood film and qPCR, and for malaria gametocyte qPCR, membrane feeding assays (MFA), HIV-I and HIV-II antigen, HBV, HCV, CMV, and EBV, malaria immune response, CBC, and biochemistry according to the study protocol. Data analysis The safety of the CHMI will be assessed by descriptive analysis of the frequency, incidence and nature of adverse events and serious adverse events arising during the study. Since this is a feasibility study conducted in 2 volunteers per dosing group, formal statistical hypothesis testing will not be used for most analyses due to the limited sample size, and only a brief Statistical Analysis Plan (SAP) will be developed and finalized prior to database lock. The study will be conducted in accordance with the current approved protocol, the International Conference on Harmonisation-Good Clinical Practice (ICH GCP), relevant regulations, and standard operating procedures. Data will be evaluated for compliance with the protocol and accuracy in relation to source documents. Following written standard operating procedures, the monitors will verify that the clinical study is conducted and data are generated, documented and reported in compliance with the protocol.

This is a follow-up study of a randomised clinical trial, called TEMPO (a double-blind randomized clinical trial investigating infant formula and human breast milk consumption), in which infants participated in their first year of life. The investigators like to know if these children develop allergies or infections in childhood and whether their feeding pattern in infancy plays a role.

The main objective of the study is to evaluate the persistence of the immunoglobulin G (IgG) antibody responses, specific to Alpha-like protein CN (AlpCN), Ribosomal Protein N (RibN), Alpha-like protein 1N (Alp1N), and Alpha-like protein 2 and 3 (Alp2-3N), after a primary vaccination with GBS-NN/NN2 in all participants.

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.

Mozobil (TM) (plerixafor injection, Genzyme/Sanofi) is a Food and Drug Administration approved medication to mobilize CD34+ hematopoietic stem cells prior to apheresis and use in autologous transplantation in non-Hodgkin lymphoma and multiple myeloma when used in conjunction with granulocyte-colony stimulating factor (G-CSF). The drug s mechanism of action is the specific and reversible inhibition of the chemokine receptor, CXCR4, expressed on CD34+ cells and other leukocytes. This inhibition interferes with the binding of stromal cell derived factor-1 (SDF-1), which is constitutively expressed on bone marrow stromal cells and appears to cause direct and indirect cellular adhesive interactions. Severe congenital neutropenia is a rare inherited disorder in which the affected individuals develop chronic or cyclical neutropenia with circulating counts below 500 cells/microliter blood. This disorder may result from a variety of genetic defects in progenitor- or neutrophil-expressed genes such as elastase, CXCR4, G6PC3, etc. Myelokathexis is the abnormal retention of mature leukocytes in the bone marrow and is seen in some types of severe chronic neutropenia such as warts, hypogammaglobulinemia, infections, and myelokathexis syndrome (WHIMS). WHIMS is a rare primary immunodeficiency, which is known to be caused by mutations that enhance CXCR4 signaling. Our hypothesis is that Mozobil(TM) can be used safely to partially block CXCR4 and treat neutropenia resulting from myelokathexis at doses considerably lower than that being used for CD34+ cell mobilization. This new treatment could also improve other aspects of the disease such as frequent infections, warts, and hypogammaglobulinemia. To test this hypothesis, we propose this trial of Mozobil (TM) in adults with WHIMS, examining safety and absolute neutrophil count as the primary endpoint. Mozobil is injected subcutaneously and will be injected via syringes (up to 84 months) or via an infusion pump (pilot trial of up to 10 subjects for a 24-month period).

This is a multi-country, open label, two-arm, parallel-group, superiority, individually randomised clinical trial involving 2,606 febrile children per country (two countries, total n=5212). The trial will compare the performance of a point-of-care rapid triage test (POC-RTT) based on suPAR levels (i.e.suPARnostic®) (in combination with IMCI-based strategies, which are the SoC) to appropriately support admission/referral vs discharge decisions during the first clinical assessment of febrile children aged 2-\<60 months compared to the standard of care based on IMCI guidelines. Febrile children meeting the study eligibility criteria will be randomly allocated (1:1) to one of the two triaging approaches (arms): 1) IMCI-based standard of care (SoC); or 2) IMCI-enhanced by suPAR levels (SoC + suPAR POC). Blood will be collected from all participants and only those randomised to the intervention arm (arm 2) will have suPAR levels determined at the POC using suPARnostic® device. At baseline, all children will undergo two clinical assessments. Primary composite endpoint of "appropriateness of discharge" will be based on the first clinical assessment, which is more representative of real-world clinical practice. However, the ultimate decision on admission/referral vs discharge will be based on the second clinical assessment, which will ensure the safest possible clinical practice in the context of a clinical trial. 1. At baseline, during the first clinical assessment, all participants will be evaluated following the SoC based on IMCI guidelines, which will guide management decisions, including clinical diagnosis and treatment. This IMCI-guideline based evaluation during this first clinical assessment will be conducted by a health worker as per routine clinical practice in the outpatient departments of each study site. 1. In the participants randomised to the control arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation alone (SoC). 2. In the participants randomised to the intervention arm, decision of admission/referral vs discharge home will be informed by IMCI-based evaluation enhanced by suPAR levels (SoC + suPAR POC). Clinicians will be instructed to admit for further observation any child with suPAR levels equal or superior to 4 ng/mL (except for confirmed malaria, that it will be equal or superior to 6 ng/mL), as these patients are at moderate or high risk of adverse outcomes and death. On the other hand, children with suPAR levels below 4 ng/mL (or below 6 ng/mL in case of confirmed malaria) will be eligible for discharge home at the criteria of the clinician, considering the signs and symptoms found, and based on IMCI guidelines. Hence, should clinicians in charge deem that any of these children still require admission, they will be instructed to continue with the admission regardless of suPAR levels. The study intervention will be implemented during the first clinical assessment, and consequently, primary composite endpoint of "appropriateness of discharge" will be based on the decision of admission/referral vs discharge home during this first clinical assessment, which is more representative of routine clinical practice in each study site. 2. All randomised participants will be also evaluated by an independent study physician in a second clinical assessment, for the implementation of a systematised clinical evaluation (IMCI-based) to uncover any danger signs or severity criteria potentially missed or misinterpreted during the first assessment. This second assessment will also include clinical variables of the clinical scores ED-PEWS, LqSOFA and LODS, as well as temperature and oxygen saturation measures. Hence, study clinicians during this second clinical assessment might be able to uncover more symptoms and signs that are admission criteria due to the tools available in the context of this clinical trial. Initially discharged patients from both arms showing a danger sign during this second assessment will be admitted, as well as those from the intervention arm with suPAR high-risk (red light) and moderate-risk (yellow light) levels, in case that the first clinician might not have adhered to the protocol during the first assessment. On the other hand, this second assessment will not overturn the decision of the first clinician if admission has been decided in case of low-risk (suPAR levels below 4 ng/mL; or below 6 ng/mL in case of confirmed malaria). This second clinical assessment will guide the ultimate decision on admission/referral vs discharge in order to ensure the safest possible clinical practice in the context of a clinical trial. Moreover, those participants with respiratory symptoms will be eligible for the respiratory tract infection (RTI) sub-study, where digital lung auscultations, a mid-turbinate nasal swab and a saliva sample will be collected. Throughout the study, all participants will receive treatment as per the routine clinical practice and SoC for each diagnosis at each study site, administered by clinical staff routinely working in the participating facilities. All participants will have follow-up evaluations by study clinicians on days 3 and 7 post-enrolment, or at any time in-between in case of clinical deterioration according to caregivers' evaluation. All participants will be also followed-up on day 28 for an interview to follow-up on serious adverse events (SAEs), as well as to collect information on secondary consultations and hospitalisation, or death. A follow-up extra visit at day 91 (month 3) can be conducted for an interview to ask for hospitalisation or death.

The goal of this clinical trial is to assess the efficacy and safety or a revised weight band tafenoquine dose in vivax malaria patients. The main question\[s\] it aims to answer are: * is a revised weight-based TQ regimen (TQRevised: target dose 7.5mg/kg) non-inferior to high dose primaquine (7mg/kg over 7 days) * is a revised weight-based TQ regimen (TQRevised: target dose 7.5mg/kg) superior to fixed dose tafenoquine (300mg) * is the tolerability and safety of TQRevised acceptable * is TQRevised acceptable and feasible Participants will receive a tafenoquine target dose 7.5mg/kg in weight bands. Researchers will compare this to patients receiving a fixed dose tafenoquine and high dose primaquine to see if safe and effective.

This is an interventional, phase 2, PoC (Proof of Concept) randomized, participant- and investigator-blinded, controlled, parallel group study, with 4 treatment arms. The purpose of this study is to assess the efficacy (anti-parasitological activity), safety, PK (pharmacokinetics), and PD (pharmacodynamics) of LXE408 in participants with CICD (chronic indeterminate Chagas disease) and chronic Chagas disease without severe cardiac or gastrointestinal dysfunction compared to placebo and to benznidazole.

The primary purpose of the study is to evaluate the safety and tolerability of single ascending oral doses of E1018 in healthy adult participants and to evaluate the pharmacokinetics (PK) of E1018 in plasma and urine after single oral dose administration.