Clinical trial NCT06413108: Safety, Pharmacokinetics, and Plasmodium Falciparum Transmission-reducing Activity of Monoclonal Antibody TB31F in Mali
Official title: A Phase 1/2a Single Centre, Randomised, Placebo-controlled, Double-blind, Dose-escalation, Age De-escalation, Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Plasmodium Falciparum Transmission-reducing Activity of Monoclonal Antibody TB31F in Malaria-exposed Malian Adults and Children
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
PHASE2
Conditions: Malaria,Falciparum
Keywords: transmission-reducing
monoclonal antibody
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Malaria Research and Training Center, Bamako, Mali
name: London School of Hygiene and Tropical Medicine
First posted: 2024-05-14
Enrollment: 165
Sex: ALL
Minimum age (years): 10
Maximum age (years): 50
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: We will perform two sequential stages of clinical research, each recruiting a distinct cohort of participants to confirm: 1. TB31F safety and 2. TB31F efficacy. The safety cohort will be composed of the three dose groups in adults (groups 1, 2 and 3) and two dose groups in children (groups 4 and 5). The efficacy cohort will be composed of two dose groups in adults and children (group 6). Participants will be randomised within each treatment group to receive a single sub-cutaneous dose of TB31F or placebo.
Primary purpose: OTHER

Brief summary: Mali faces a significant challenge with malaria, particularly among its younger population. While existing measures like seasonal chemoprevention and vaccination have shown efficacy, further innovations are necessary to combat this disease. The monoclonal antibody TB31F shows promise in reducing the transmission of malaria. This clinical trial will evaluate the safety and efficacy of the monoclonal antibody TB31F.


Eligibility criteria: SAFETY COHORT (STUDY ARM 1-5)

Inclusion Criteria:

1. Written/signed informed consent
2. Adult cohorts: 18-50 years of age
3. School-age children cohorts: 10-15 years of age
4. Haemoglobin ≥10 g/dL
5. Non-lactating females of childbearing potential agree to the use of continuous adequate contraception for 28 days after having received investigational product
6. Subject agrees to refrain from blood donation during the study and for 5 months after having received investigational product
7. Subjects are available to attend all study visits
8. In opinion of the investigator, the subject can and will comply with the requirements of the protocol

Exclusion Criteria:

1. Women who are pregnant (tested at baseline and at day 28 after administration of investigational product by urine and/or serum pregnancy testing (β-hCG)) or lactating
2. Symptomatic malaria
3. Current acute or chronic disease, including clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by history or physical examination
4. Clinically significant abnormal blood chemistries and haematology
5. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 year
6. History of adverse reactions to monoclonal antibodies
7. Administration of immunoglobulin and/or blood products within the three months preceding the first dose of the investigational product or planned administration during the study period
8. 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

EFFICACY COHORT (STUDY ARM 6)

Inclusion Criteria:

1. Written/signed informed consent
2. 10-50 years of age
3. Haemoglobin ≥10 g/dL
4. Non-lactating females of childbearing potential agree to the use of continuous adequate contraception for 28 days after having received investigational product
5. Subject agrees to refrain from blood donation during the study and for 5 months after having received investigational product
6. Subjects are available to attend all study visits
7. In opinion of the investigator, the subject can and will comply with the requirements of the protocol
8. Asymptomatic P. falciparum mono-infection with asexual parasite densities \<3000 parasites/µL
9. Presence of P. falciparum gametocytes on thick blood film at a density \>16 gametocytes/µL

Exclusion Criteria:

1. Women who are pregnant (tested at baseline and at day 28 after administration of investigational product by urine and/or serum pregnancy testing (β-hCG)) or lactating
2. Symptomatic malaria
3. Current acute or chronic disease, including clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by history or physical examination
4. Clinically significant abnormal blood chemistries and haematology
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
6. History of adverse reactions to monoclonal antibodies
7. Administration of immunoglobulin and/or blood products within the three months preceding the first dose of the investigational product or planned administration during the study period
8. 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
9. Use of anti-malarial drug treatment in the last 14 days
10. Prior receipt of an antimalarial monoclonal antibody
11. Prior receipt of a P. falciparum transmission-blocking vaccine

Primary outcomes:
measure: Occurrence of at least possibly related solicited local and systemic adverse events
timeFrame: within 7 days of monoclonal antibody TB31F administration
measure: Occurrence of at least possibly related unsolicited adverse events
timeFrame: within 28 days of monoclonal antibody TB31F administration
measure: Occurrence of at least possibly related serious adverse events
timeFrame: from enrollment to the end of follow-up at 28 or 84 days
measure: Terminal serum half-life (t½) of monoclonal antibody TB31F in serum
timeFrame: day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
measure: Maximum observed serum concentration (Cmax) of monoclonal antibody TB31F in serum
timeFrame: day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
measure: Time to reach maximum serum concentration (tmax) of monoclonal antibody TB31F in serum
timeFrame: day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
measure: Accumulation index (Racc) of monoclonal antibody TB31F in serum
timeFrame: day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
measure: Area under the serum concentration-time curve (AUC0-τ, AUC0-t and AUC) of monoclonal antibody TB31F in serum
timeFrame: day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
measure: Within-group percent reduction in the proportion of mosquitoes infected at day 5 post-treatment compared to baseline (day 0), assessed through direct membrane feeding assays and measured as oocyst prevalence
timeFrame: day 0 [baseline] & 5
Secondary outcomes:
measure: Within-group percent reduction in the proportion of mosquitoes infected in direct skin feeding assay (DSF), compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, and 5
measure: Within-group percent reduction in the proportion of mosquitoes infected in direct membrane feeding assays (DMFA), compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, 5, and 14
measure: Mosquito infection prevalence, assessed by direct skin feed and measured as the proportion dissected mosquitoes with any number of oocysts, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, and 5
measure: Mosquito infection prevalence, assessed by DMFA and measured as the proportion dissected with any number of oocysts, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, 5, and 14
measure: Mosquito infection intensity, assessed by direct skin feed and measured as the number of oocysts in dissected mosquitoes, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, and 5
measure: Mosquito infection intensity, assessed by DMFA and measured as the average number of oocysts in dissected mosquitoes, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, 5, and 14
measure: Participant infection prevalence, assessed by DSF as the proportion of individuals infectious to any number of mosquitoes, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, and 5
measure: Participant infection prevalence, assessed by DMFA as the proportion of individuals infectious to any number of mosquitoes, compared within groups between baseline and all feeding time points, and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 1, 5, and 14
measure: Transmission-reducing activity in school-age children and adults, measured as the percent reduction in mean oocyst intensity compared to experimental controls, compared within groups and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
Other outcomes:
measure: Total serum immunoglobulin G level
timeFrame: day 0 [baseline]
measure: Serum leptin level
timeFrame: day 0 [baseline]
measure: Total protein level
timeFrame: day 0 [baseline]
measure: Albumin level
timeFrame: day 0 [baseline]
measure: Pre-albumin level
timeFrame: day 0 [baseline]
measure: Human genotype analysis at baseline (G6PD, CYP2D6, HBB)
timeFrame: day 0 [baseline]
measure: Plasma biomarkers (i.e. antibodies) at baseline and at post-administration timepoints
timeFrame: day 0 [baseline]
measure: Transmission-blocking activity measured as the percent reduction in mosquito infection prevalence compared to experimental controls, compared within and between groups at all feeding timepoints.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: The concentration of TB31F in serum that provides >80% reduction in the average proportion of infected mosquitoes as measured in direct skin feeding assay after TB31F administration.
timeFrame: day 0 [baseline], 1, and 5.
measure: The concentration of TB31F in serum that provides >80% reduction in the average proportion of infected mosquitoes as measured in direct membrane feeding assays after TB31F administration.
timeFrame: day 0 [baseline], 1, 5, and 14.
measure: The concentration of TB31F in serum that provides >80% transmission blocking activity relative to experimental controls as measured in standard membrane feeding assay after TB31F administration.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: Measure the concentration of TB31F in serum that provides >80% reduction in the average mosquito infection intensity (oocyst number) as measured in direct skin feeding assay after TB31F administration.
timeFrame: day 0 [baseline], 1, and 5.
measure: The concentration of TB31F in serum that provides >80% reduction in the average mosquito infection intensity (oocyst number) as measured in direct membrane feeding assays after TB31F administration.
timeFrame: day 0 [baseline], 1, 5, and 14.
measure: The concentration of TB31F in serum that provides >80% transmission reducing activity relative to experimental controls as measured in standard membrane feeding assay after TB31F administration.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: The correlation between naturally acquired anti-gametocyte immune responses and naturally acquired functional TRA on mosquito infection prevalence, assessed by SMFA and measured as the proportion dissected mosquitoes with any number of oocysts.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: The correlation between naturally acquired anti-gametocyte immune responses and naturally acquired functional transmission-reducing activity on mosquito infection intensity, assessed by SMFA and measured as the number of oocysts in dissected mosquitoes.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: The correlation between naturally acquired anti-gametocyte immune responses and naturally acquired functional TRA on participant infectivity, assessed by SMFA as the proportion of individuals infectious to any number of mosquitoes.
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
measure: Parasite genotype analysis (amplicon and whole genome sequencing)
timeFrame: day 0 [baseline]
measure: Antibodies and parasite protein in plasma at baseline and at post-administration timepoints
timeFrame: day 0 [baseline], 5, 14, 28, 56, and 84
Locations:
city: Bamako
country: Mali
facility: Faculty of Pharmacy and Faculty of Medicine and Dentistry, University of Sciences Techniques and Technologies of Bamako
state: Point G
Study officials:
References: