A study to investigate the dose of Bilharzia worms that can be safely used to infect humans as a first step to enable testing Bilharzia vaccines

• Register: ISRCTN
• Last refreshed on: 28 June 2021
• Main ID: ISRCTN14033813
• Date of registration: 01/02/2021
• Prospective Registration: Yes
• Primary sponsor: London School of Hygiene & Tropical Medicine
• Public title: A study to investigate the dose of Bilharzia worms that can be safely used to infect humans as a first step to enable testing Bilharzia vaccines
• Scientific title: Establishing a single-sex controlled human Schistosoma mansoni infection model for Uganda: safety and dose finding
• Date of first enrolment: 01/01/2022
• Target sample size: 66
• Recruitment status: Ongoing
• URL: http://isrctn.com/ISRCTN14033813
• Study type: Interventional
• Study design: Single-centre open-label dose-escalation trial (Other)
• Phase: Not Applicable

Countries of recruitment

Uganda

Contacts

• Name: Alison Elliott

• Name: Richard Sanya

Key inclusion & exclusion criteria

Inclusion criteria:
1. Volunteer is aged =18 and =45 years and in good health
2. Volunteer is able to communicate well with the research team members and is available to attend all study visits
3. Volunteer has an adequate understanding of the procedures of the study and agrees to abide strictly thereby
4. Volunteer will remain within Uganda during the study period and is reachable by mobile telephone from until at least week 16 of the study period
5. Volunteer understands the need to avoid contact with waterbodies where Schistosoma is transmitted and can demonstrate that they are able and willing to do so for the full 12-16 week period until the controlled infection has been cured
6. Volunteer agrees to refrain from blood donation throughout the study period
7. For a female volunteer: volunteer agrees to use adequate contraception and not to breastfeed for the duration of the study
8. Volunteer has signed informed consent

Exclusion criteria:
1. Evidence of current Schistosoma infection based on highly sensitive CAA assay (at a conservative cut-off level of >0.5 pg/ml)
2. Evidence of malaria or of intestinal helminth infections (if identified, these will be treated and the volunteer may be reconsidered for inclusion)
3. Any history, or evidence at screening, of clinically significant symptoms, physical signs or abnormal laboratory values suggestive of systemic conditions, such as cardiovascular, pulmonary, renal, hepatic, neurological, dermatological, endocrine, malignant, haematological, infectious, immune-deficient, psychiatric and other disorders, which could compromise the health of the volunteer during the study or interfere with the interpretation of the study results. These include, but are not limited to, any of the following. Note that volunteers may be reconsidered for inclusion following recovery from treatable conditions:
3.1. Temperature =37.5°C/99.5°F
3.2. Body weight <50 kg or Body Mass Index (BMI) <18.0 or >30.0 kg/m² at screening
3.3. Positive HIV, HBV or HCV screening tests
3.4. The use of immune modifying drugs within three months prior to study onset (inhaled and topical corticosteroids and oral anti-histamines exempted) or expected use of such during the study period
3.5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years
3.6. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year
3.7. History of drug or alcohol abuse interfering with normal social function in the period of 1 year prior to study onset
3.8. Any clinically significant abnormalities (including extended QT interval) on electrocardiogram
4. The chronic use of any drug known to interact with praziquantel, artesunate or lumefantrine metabolism (e.g. phenytoïn, carbamazepine, phenobarbital, primidone, dexamethasone, rifampicin, cimetidine, flecainide, metoprolol, imipramine, amitriptyline, clomipramine, class IA and III antiarrhythmics, antipsychotics, antidepressants, macrolides, fluoroquinolones, imidazole- and triazole antimycotics, antihistamines). Because lumefantrine may cause extension of QT-time, chronic use of drugs with effect on QT interval are excluded from the study
5. For female volunteers: positive urine pregnancy test at screening, or breastfeeding
6. Known hypersensitivity to or contra-indications (including co-medication) for use of praziquantel, artesunate or lumefantrine
7. Participation in another research study involving receipt of an investigational product in the 30 days preceding enrolment, or planned use during the study period
8. Being an employee or student of the Uganda Virus Research Institute or its campus partners, or of Entebbe Hospital
9. Volunteer who, in the opinion of the investigator, does not fully understand the purpose of the study or requirements for participation or is unlikely to adhere to the requirements of the study


Age minimum:
Age maximum:
Gender: Both

Health Condition(s) or Problem(s) studied

Schistosomiasis
Infections and Infestations
Schistosomiasis [bilharziasis]

Intervention(s)

Healthy human volunteers will be enrolled from two settings; one with minimal prior schistosome exposure and another with intense prior exposure, both in Uganda. In each setting, groups of volunteers will be dermally exposed to single-sex (male) cercariae once at doses of between 10 and 30 cercariae. Depending on the outcome of the low dose infection, the dose will be escalated or additional volunteers will be exposed to the same number of cercariae. Volunteers will undergo intensive follow-up for 24 weeks and a late follow-up time point at 52 weeks. They will visit the clinical trial centre weekly after infection for 12 weeks. After this, two-weekly visits will continue until week 24. A final follow up visit will be after one year. During the visits, adverse events will be recorded, levels of Schistosoma mansoni circulating anodic antigen (CAA) will be measured and samples obtained for immunological analyses. Immediately CAA is detected (expected around 6 to 8 weeks after infection) the volunteers will be treated with praziquantel to cure the Schistosoma infection. Praziquantel may be repeated 4 weeks later if CAA levels do not fall to zero. Volunteers will be required to avoid contact with potentially Schistosoma mansoni-contaminated water until the controlled infection has been shown to have been effectively cured, potentially a period of up to 14 weeks. The trial is estimated to last 30 months.

Primary Outcome(s)

1. Frequency and magnitude of adverse events after controlled human Schistosoma mansoni infection with male cercariae measured using a diary kept by the volunteer and a questionnaire filled out at every visit documenting the participants’ symptoms and signs. These data will be collected at baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 20, 22, 24 and 52 weeks
2. Number of male cercariae at which 100% of volunteers show patent infection, i.e. detectable Schistosoma mansoni circulating anodic antigen (CAA), measured using the predefined dose of cercariae administered and a serum CAA assay. A patent infection will be defined as a positive serum CAA test (>1.0 pg/ml) at any time between 0 and 12 weeks following infection with cercariae. CAA will be measured at baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 weeks

Secondary Outcome(s)

1. Time to positive serum and urine CAA (Circulating Anodic Antigen) test measured using a serum and urine CAA assay after infection at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 weeks
2. Comparison of the height of the peak serum CAA concentration in different dose groups measured using a serum CAA assay at baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 weeks
3. Humoral (antibody) responses directed against Schistosoma mansoni antigens measured using antibody assays by immunofluorescence and/or enzyme-linked immunosorbent assays (ELISAs) and/or antibody arrays for specific Schistosoma mansoni proteins or glycans at baseline, 4, 8, 12, 14, 16, 18, 20, 22, 24 and 52 weeks
4. Cellular responses directed against Schistosoma mansoni antigens measured using multi-parameter flow cytometry, mass cytometry time-of-flight (CyToF) and enzyme-linked Immune absorbent spot (ELISPOT) assays with or without using Schistosoma mansoni-specific in vitro stimulation at baseline, 4, 8, 12, 14, 16, 18, 20, 22, 24 and 52 weeks
5. Metabolic changes before and after controlled human Schistosoma mansoni infection with male Schistosoma mansoni cercariae measured by metabolic profiling of serum and urine samples at baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 16, 18, 20, 22, 24 and 52 weeks
6. Changes in microbiome after controlled human Schistosoma mansoni infection with male Schistosoma mansoni cercariae measured using bioinformatic sequencing pipelines at baseline, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 20, 22, 24 and 52 weeks

Secondary ID(s)

Nil known

Source(s) of Monetary Support

Wellcome Trust

Ethics review

Status:
Approval date:
Contact:

1. Approved 06/04/2020, Uganda Virus Research Institute Research Ethics Committee (Plot 51-59 Nakiwogo Road, Entebbe; PO Box 49 Entebbe, Uganda; [phone]; [e-mail]), ref: GC/137/20/04/773 2. Approved 17/11/2020, Uganda National Council for Science and Technology (Plot 6 Kimera Road, Kampala; P. O. Box 6884 Kampala, Uganda; [phone]; [e-mail]), ref: HS697ES 3. Approval pending, London School of Hygiene an

Results

• Date Completed: 31/05/2023