Safety, Pharmacokinetics, and Plasmodium Falciparum Transmission-reducing Activity of Monoclonal Antibody TB31F in Mali

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Malaria,Falciparum
• Intervention / Treatment: Other: Normal saline; Drug: TB31F

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Phase 2; Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Quadruple

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: 1A: control; 0.2 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 1B: 10 mg TB31F; 0.2 mL (10 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Placebo Comparator: 2A: control; 2 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 2B:100 mg TB31F; 2 mL (100 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Placebo Comparator: 3A: control; 4 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 3B: 200 mg TB31F; 4 mL (200 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Placebo Comparator: 4A: control; 0.2 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 4B: 10 mg TB31F; 0.2 mL (10 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Placebo Comparator: 5A: control; 2.0 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 5B: 100 mg TB31F; 2.0 mL (100 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Placebo Comparator: 6A: control; 0.6 or 2.0 mL normal saline	Other: Normal saline; normal saline as control (placebo)
Experimental: 6B: 30 mg TB31F; 0.6 mL (30 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F
Experimental: 6C: 100 mg TB31F; 2.0 mL (100 mg) TB31F	Drug: TB31F; transmission-blocking monoclonal antibody TB31F

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Occurrence of at least possibly related solicited local and systemic adverse events	within 7 days of monoclonal antibody TB31F administration
Occurrence of at least possibly related unsolicited adverse events	within 28 days of monoclonal antibody TB31F administration
Terminal serum half-life (t½) of monoclonal antibody TB31F in serum	day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
Maximum observed serum concentration (Cmax) of monoclonal antibody TB31F in serum	day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
Time to reach maximum serum concentration (tmax) of monoclonal antibody TB31F in serum	day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
Accumulation index (Racc) of monoclonal antibody TB31F in serum	day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
Area under the serum concentration-time curve (AUC0-τ, AUC0-t and AUC) of monoclonal antibody TB31F in serum	day 0 [baseline], day 1, day 5, day 7, day 14, day 21, day 28, day 42, day 56, day 84.
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	day 0 [baseline] & 5

Secondary Outcome Measures

Outcome Measure	Time Frame
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.	day 0 [baseline], 1, and 5
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.	day 0 [baseline], 1, 5, and 14
Mosquito infection prevalence, assessed by direct skin feed 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.	day 0 [baseline], 1, and 5
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.	day 0 [baseline], 1, 5, and 14
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.	day 0 [baseline], 1, and 5
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.	day 0 [baseline], 1, 5, and 14
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.	day 0 [baseline], 1, and 5
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.	day 0 [baseline], 1, 5, and 14
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.	day 0 [baseline], 5, 14, 28, 56, and 84

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total serum immunoglobulin G level	Quantification of the effect of nutritional and protein metabolism status	day 0 [baseline]
Serum leptin level	Quantification of the effect of nutritional and protein metabolism status	day 0 [baseline]
Total protein level	Quantification of the effect of nutritional and protein metabolism status	day 0 [baseline]
Albumin level	Quantification of the effect of nutritional and protein metabolism status	day 0 [baseline]
Pre-albumin level	Quantification of the effect of nutritional and protein metabolism status	day 0 [baseline]
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.	To assess the transmission-blocking activity of participant serum after TB31F administration as assessed in the Standard Membrane Feeding Assay (SMFA) at each dose level in adults and school-age children	day 0 [baseline], 5, 14, 28, 56, and 84
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.		day 0 [baseline], 1, and 5.
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.		day 0 [baseline], 1, 5, and 14.
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.		day 0 [baseline], 5, 14, 28, 56, and 84
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.		day 0 [baseline], 1, and 5.
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.		day 0 [baseline], 1, 5, and 14.
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.		day 0 [baseline], 5, 14, 28, 56, and 84

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: London School of Hygiene and Tropical Medicine; Malaria Research and Training Center, Bamako, Mali

Study record dates

Study Major Dates

• Study Start (Estimated): June 1, 2024
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): January 1, 2025

Study Registration Dates

• First Submitted: May 3, 2024
• First Submitted That Met QC Criteria: May 8, 2024
• First Posted (Actual): May 14, 2024

Study Record Updates

• Last Update Posted (Actual): May 14, 2024
• Last Update Submitted That Met QC Criteria: May 8, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: monoclonal antibody; transmission-reducing
• Additional Relevant MeSH Terms: Infections; Vector Borne Diseases; Parasitic Diseases; Protozoan Infections; Mosquito-Borne Diseases; Malaria; Malaria, Falciparum
• Other Study ID Numbers: TB31F Mali

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Sharing Supporting Information Type: SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No