Controlled Human Malaria Infection Model for Evaluation of Transmission-blocking Interventions - Study 2

Study Overview
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Brief Summary
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This is a single-center, open label study. The primary aim of this project is to develop a controlled human malaria infection transmission model (CHMI-trans) or challenge model to evaluate the capacity of vaccines, biologics (monoclonal antibodies, or mAbs), and drugs to block malaria parasite transmission by assessing infectiousness of Plasmodium falciparum (Pf) gametocyte carriers for Anopheles mosquitoes.

Detailed Description
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A total of 24 volunteers, in two cohorts (n=12), will be randomly assigned to two groups per cohort (n=6). Cohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes (groups 1 and 2). Cohort B will be subjected to a standard blood stage challenge with  2,800 Pf-infected erythrocytes by intravenous injection (groups 3 and 4). Treatment is subsequently initiated to induce gametocytemia (treatment 1, T1) and to clear pathogenic asexual parasites whilst leaving gametocytes unaffected (treatment 2 and 3, T2 and T3). At the end of the study, treatment of all parasite stages is provided following national treatment guidelines (end treatment, ET). Once malaria infections are detected by 18S qPCR positive (sporozoite challenge) or on day 8 (blood stage challenge), all volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Using blood samples taken twice daily, the initial clearance of parasitemia will be carefully monitored. After T1, volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. On day 21 or when a recrudescence occurs after T2, volunteers in group 1 and 3 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg) and group 2 and 4 (LD-PIP/LD-PIP2/SP) with sulfadoxine-pyrimethamine (1000mg/50mg). These treatment regimens cure asexual parasitemia while leaving immature and mature gametocytes unaffected. To ensure the radical clearance of all parasite stages, all volunteers will receive a final treatment (ET) according to national guidelines with atovaquone/proguanil (Malarone®) on day 36. Daily blood samples will allow detailed quantification of gametocytes, gametocyte sex ratio and ex vivo assessments of gametocyte fitness. Additionally, blood samples will be obtained for Direct Membrane Feeding Assay (DMFA) and volunteers will be subjected to Direct Skin Feeding Assays (DFA). These assays will provide evidence on the infectivity of volunteers.

Official Title
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Controlled Human Malaria Infection Study to Assess Gametocytemia and Mosquito Transmissibility in Participants Challenged With Plasmodium Falciparum by Sporozoite or Blood Stage Challenge to Establish a Model for the Evaluation of Transmission-blocking Interventions

Conditions
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Malaria,Falciparum, Gametocytes, Controlled Human Malaria Infection, Transmission

Intervention / Treatment
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* Drug: Piperaquine (low dose)
* Drug: Piperaquine (high dose)
* Drug: Sulfadoxine pyrimethamine
* Drug: Atovaquone Proguanil
* Other: malaria challenge infection, P. falciparum 3D7
* Other: Blood stage malaria challenge infection, P. falciparum 3D7


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: In order to be eligible to participate in this study, a subject must meet all of the following criteria: Subject is aged ≥ 18 and ≤ 35 years and in good health. Subject has adequate understanding of the procedures of the study and is able and willing (in the investigator's opinion) to comply with all study requirements. Subject is willing to complete an informed consent questionnaire and is able to answer all questions correctly. Subject is able to communicate well with the investigator and is available to attend all study visits, lives in proximity to the trial centre (<10 km) or (if >10km) is willing to stay in a hotel close to the trial centre during part of the study (from day 4 (blood stage challenge) 5 (sporozoite challenge) post-infection until T1+4 provided that the subject has had 2 consecutive negative 18S qPCR tests (at least 24 hours apart) following T1 treatment; or until day T3+3). The subject will remain within the Netherlands during the challenge period, will not travel to a malaria-endemic area during the study period, and is reachable (24/7) by mobile telephone throughout the entire study period. Subject agrees to their general practitioner being informed and contacted about their participation in the study and agrees to sign a form to request the release by their General Practitioner (GP), and medical specialist when necessary, to the investigator(s), of any relevant medical information concerning possible contra-indications for participation in the study. The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period and for a defined period thereafter according to current Sanquin guidelines. For female subjects: subject agrees to use continuous adequate contraception** and not to breastfeed for the duration of study. Subject agrees to refrain from intensive physical exercise (disproportionate to the subject's usual daily activity or exercise routine) during the malaria challenge period until day 38 after infection. Subject agrees to avoid additional triggers that may cause elevations in liver enzymes including alcohol from baseline up to 1 week post treatment (T3). Subject has signed written informed consent to participate in the trial. (*Acceptable forms of contraception include: established use of oral, injected or implanted hormonal contraceptives; intrauterine device or intrauterine system; barrier methods (condoms or diaphragm with additional spermicide); male partner's sterilisation (with appropriate post-vasectomy documentation of absence of sperm in the ejaculate); true abstinence when this is in line with the preferred and usual lifestyle of the subject; Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.) Exclusion Criteria: A potential subject who meets any of the following criteria will be excluded from participation in this study: 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, immunodeficient, 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. 1.1. Body weight <50 kg or Body Mass Index (BMI) <18 or >30 kg/m2 at screening. 1.2. A heightened risk of cardiovascular disease, as determined by: an estimated ten year risk of fatal cardiovascular disease of ≥5% at screening, as determined by the Systematic Coronary Risk Evaluation (SCORE); history, or evidence at screening, of clinically significant arrhythmia's, prolonged QT-interval or other clinically relevant ECG abnormalities; or a positive family history of cardiac events in 1st or 2nd degree relatives <50 years old. 1.3. A medical history of functional asplenia, sickle cell trait/disease, thalassaemia trait/disease or G6PD-deficiency. 1.4. History of epilepsy in the period of five years prior to study onset, even if no longer on medication. 1.5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV) 1.6. Chronic use of i) immunosuppressive drugs, ii) antibiotics, iii) or other 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. 1.7. Any recent or current systemic therapy with an antibiotic or drug with potential anti-malarial activity (chloroquine, doxycycline, tetracycline, piperaquine, benzodiazepine, flunarizine, fluoxetine, tetracycline, azithromycin, clindamycin, erythromycin, hydroxychloroquine, etc.) (allowable timeframe for use at the Investigator's discretion). 1.8. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years. 1.9. Any history of treatment for severe psychiatric disease by a psychiatrist in the past year. 1.10. History of drug or alcohol abuse interfering with normal social function in the period of one year prior to study onset, positive urine toxicology test for cocaine or amphetamines at screening or at inclusion, or positive urine toxicology test for cannabis at inclusion. For female subjects: positive urine pregnancy test at screening and/or at the baseline visit. Abnormal ALT/AST values on baseline Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study. Known hypersensitivity to or contra-indications (including co-medication) for use of sulfadoxine-pyrimethamine, piperaquine, chloroquine, Malarone®, artemether-lumefantrine, primaquine or history of severe (allergic) reactions to mosquito bites. Participation in any other clinical study in the 30 days prior to the start of the study or during the study period. Being an employee or student of the department of Medical Microbiology of the Radboudumc or the department of Internal Medicine. Any other condition or situation that would, in the opinion of the investigator, place the subject at an unacceptable risk of injury or render the subject unable to meet the requirements of the protocol. For cohort B (blood stage challenge): Received a blood transfusion in the past. For cohort B (blood stage challenge): Women of childbearing potential with a screening test positive for erythrocyte anti-Rh(c) and/or anti-Rh(e) antibodies.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1 (Cohort A) LD-PIP/LD-PIP2/PIP<br>Cohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 1 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg). | Drug: Piperaquine (low dose)<br>* subcurative regimen (480 mg)<br>* Other names: piperaquine phosphate;Drug: Piperaquine (high dose)<br>* Curative regimen (960mg)<br>* Other names: piperaquine phosphate;Drug: Atovaquone Proguanil<br>* Curative regimen (1000/400 mg, for 3 days)<br>* Other names: Malarone;Other: malaria challenge infection, P. falciparum 3D7<br>* malaria challenge infection by P. falciparum 3D7-infected mosquito bites<br>* Other names: 3D7 Plasmodium falciparum;|
| Experimental: Group 2 (Cohort A) LD-PIP/LD-PIP2/SP<br>Cohort A will be subjected to a standard controlled human malaria infection (CHMI) delivered by five Pf-infected mosquitoes. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 2(LD-PIP/LD-PIP2/SP) will be curatively treated with sulfadoxine-pyrimethamine (1000mg/50mg). | Drug: Piperaquine (low dose)<br>* subcurative regimen (480 mg)<br>* Other names: piperaquine phosphate;Drug: Sulfadoxine pyrimethamine<br>* Curative regimen (1000mg/50mg)<br>* Other names: Fansidar;Drug: Atovaquone Proguanil<br>* Curative regimen (1000/400 mg, for 3 days)<br>* Other names: Malarone;Other: malaria challenge infection, P. falciparum 3D7<br>* malaria challenge infection by P. falciparum 3D7-infected mosquito bites<br>* Other names: 3D7 Plasmodium falciparum;|
| Experimental: Group 3 (Cohort B) LD-PIP/LD-PIP2/PIP<br>Cohort B will be subjected to a standard blood stage challenge with  2,800 Pf-infected erythrocytes by intravenous injection. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 3 (LD-PIP/LD-PIP2/PIP) will be curatively treated with piperaquine (960mg) | Drug: Piperaquine (low dose)<br>* subcurative regimen (480 mg)<br>* Other names: piperaquine phosphate;Drug: Piperaquine (high dose)<br>* Curative regimen (960mg)<br>* Other names: piperaquine phosphate;Drug: Atovaquone Proguanil<br>* Curative regimen (1000/400 mg, for 3 days)<br>* Other names: Malarone;Other: Blood stage malaria challenge infection, P. falciparum 3D7<br>* P. falciparum 3D7-infected human erythrocytes administered intravenously for the purpose controlled human malaria infection.<br>* Other names: P. falciparum 3D7-infected human erythrocytes;|
| Experimental: Group 4 (Cohort B) LD-PIP/LD-PIP2/SP<br>Cohort B will be subjected to a standard blood stage challenge with  2,800 Pf-infected erythrocytes by intravenous injection. All volunteers will be treated with a single oral subcurative low-dose of piperaquine (LD-PIP, 480 mg, T1). Volunteers will receive a second treatment (T2, LD-PIP2, 480mg) if a recrudescence of asexual parasitemia occurs before day 21 post challenge infection. Volunteers in group 4 (LD-PIP/LD-PIP2/SP) will be curatively treated with sulfadoxine-pyrimethamine (1000mg/50mg). | Drug: Piperaquine (low dose)<br>* subcurative regimen (480 mg)<br>* Other names: piperaquine phosphate;Drug: Sulfadoxine pyrimethamine<br>* Curative regimen (1000mg/50mg)<br>* Other names: Fansidar;Drug: Atovaquone Proguanil<br>* Curative regimen (1000/400 mg, for 3 days)<br>* Other names: Malarone;Other: Blood stage malaria challenge infection, P. falciparum 3D7<br>* P. falciparum 3D7-infected human erythrocytes administered intravenously for the purpose controlled human malaria infection.<br>* Other names: P. falciparum 3D7-infected human erythrocytes;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events in the CHMI-trans Model | Frequency of adverse events in the CHMI-trans model. | up to day 51 after challenge infection | 
| Gametocyte Prevalence | Number of individuals in each study arm that show prevalence of gametocytes as defined by quantitative reverse-transcriptase PCR (qRT-PCR) for CCp4 (female) and PfMGET (male) mRNA with a threshold of 5 gametocytes/mL for positivity. | up to day 51 after challenge infection | 
| Magnitude of Adverse Events in the CHMI-trans Model | symptoms will be ranked as (1) mild, (2) moderate, or (3) severe, depending on their intensity according to the following scale: Mild (grade 1): awareness of symptoms that are easily tolerated and do not interfere with usual daily activity Moderate (grade 2): discomfort that interferes with or limits usual daily activity Severe (grade 3): disabling, with subsequent inability to perform usual daily activity, resulting in absence or required bed rest | up to day 51 after challenge infection | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak Density Gametocytes | Peak density of gametocytes by qRT-PCR. | up to day 51 after challenge infection | 
| AUC Gametocytes | The area under the curve of gametocyte density versus time. The median AUC was calculated for both cohorts. Since onset of gametocytaemia differs depending on method of infection a window of 15 days was used to calculate AUC, from the time-point where a minimum of 50% of participants within a cohort had detectable gametocytemia. | up to day 51 after challenge infection | 
| Gametocyte Commitment | The gametocyte commitment rate is estimated by dividing the peak gametocyte by the peak of asexual parasites. | up to day 51 after challenge infection | 
| Gametocyte Sex-ratio | Proportion of male gametocytes | up to day 51 after challenge infection | 
| Number of Participants Infectious for Mosquitoes Through DFA | Prevalence of gametocyte infectiousness for Anopheles mosquitoes through Direct Feeding Assays (Direct Skin Feeding Assay, DFA). | up to day 51 after challenge infection |