Safety, Tolerability, and Pharmacokinetics and Pharmacody... | NCT04238689

Status Module

Name	Class
The PATH Malaria Vaccine Initiative (MVI)	OTHER

Description Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Group 1 - 0.1mg/kg TB31F	Experimental	0.1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. Subjects will be observed for the occurrence of any adverse events. There will be a minimum of 48 hours between TB31F administration to each subsequent volunteer. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising.	Biological: TB31F
Group 2 - 1mg/kg TB31F	Experimental	1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising.	Biological: TB31F
Group 3 - 3mg/kg TB31F	Experimental	3 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising.

Name	Type	Description	Arm Group Labels	Other Names
TB31F	Biological	Monoclonal antibody	Group 1 - 0.1mg/kg TB31F Group 2 - 1mg/kg TB31F Group 3 - 3mg/kg TB31F Group 4 - 10mg/kg TB31F

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Number and Severity of Adverse Events After TB31F Administration	Number and severity of solicited local adverse events of all severities from first product administration through day 7; Number and severity of solicited general adverse events and clinically significant hematological and biochemical laboratory abnormalities from first product administration through day 28; Number and severity of unsolicited adverse events from first product administration through end of study; Occurrence of serious adverse events from first product administration through end of study	Throughout study: solicited local adverse events (day 0 - day 7); solicited general adverse events and clinically significant laboratory abnormalities (day 0 - day 28); unsolicited adverse events (day 0 - day 84), serious adverse events (day 0 - day 84)

Secondary Outcomes

Measure	Description	Time Frame
Serum Concentration of TB31F	The serum concentration of TB31F will be measured in all subjects throughout the study (until day 84) by Pfs48/45 antigen ELISA.	All groups: 6 hours, 24 hours, 48 hours, day 7, day 14, day 21, day 28, day 56, day 84. Groups 1-4 only: end of infusion, 1 hour, 3 hours. Group 5 only: day 4 and day 10.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Subject must sign written informed consent to participate in the trial.
Subject is able to understand planned study procedures and demonstrate comprehension of the protocol procedures and knowledge of study by passing a quiz (assessment of understanding).
In the opinion of the investigator, the subject can and will comply with the requirements of the protocol.
Subjects are available to attend all study visits and are reachable by phone throughout the entire study period from day -1 until day 84 (end of study).
The subject will remain within reasonable travelling distance from the study center from day -1 until day +7 after mAb TB31F infusion.
Subject is a male or non-pregnant and non-lactating female age ≥ 18 and ≤ 35 years and in good health at time of mAb infusion.
Subject agrees to their general practitioner (GP) being informed about participation in the study and agrees to sign a form to request the release by their GP, and medical specialist when necessary, of any relevant medical information concerning possible contra-indications for participation in the study to the investigator(s).
The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period according to current Sanquin guidelines.
Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current bilateral tubal ligation or occlusion, hysterectomy, bilateral ovariectomy or post-menopause. All subjects must agree to use continuous adequate contraception until 2 months after completion of the study. Female subjects must agree not to breastfeed from 30 days prior to mAb infusion until 2 months after completion of the study. Female subject must have a negative pregnancy test at the inclusion visit.

Exclusion Criteria:

Acute or chronic disease at time of TB31F administration, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory screening tests:
1. Acute disease is defined as the presence of a moderate or severe illness with or without fever. Subjects with a minor illness on the day of TB31F administration will be (temporarily) excluded from participation, but may be re-evaluated for inclusion at a later date. Subjects with a positive SARS-CoV2 test at inclusion will be (temporarily) excluded from participation but may be re-evaluated for inclusion at a later date (following current Radboudumc guidelines).
2. Fever is defined as an oral, axillary or tympanic temperature ≥ 38.0°C (100.4°F). The preferred route for recording temperature in this study will be oral.
3. Any abnormal and clinically significant baseline laboratory screening tests of alanine aminotransferase, aspartate aminotransferase, creatinine, hemoglobin, platelet count or total white blood cell count, as defined in the protocol according to the FDA Toxicity Grading Scale for Healthy Adult and Adolescent Subjects Enrolled in Preventative Vaccine Clinical Trials.
History of malignancy of any organ system (other than localized basal cell carcinoma of the skin), treated or untreated, within the past 5 years.
Chronic use of i) immunosuppressive drugs, 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.
Positive urine toxicology test for cannabis, cocaine or amphetamines at screening or at inclusion.
Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV).
Use of any investigational or non-registered product (drug or vaccine) during the study period other than the study product.
Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.
Prior receipt of an investigational antimalarial monoclonal antibody.
History of adverse reactions to monoclonal antibodies.
Administration of immunoglobulin and/or any blood products within the three months preceding the first dose of study mAb or planned administration during the study period.
Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study or Controlled Human Malaria Infection.
Body weight >= 115 kg
Being an employee or student of the department of Medical Microbiology or Medium Care of the Radboudumc, or a person otherwise related to the investigator other than a professional relationship for clinical trial purpose only.
History of drug or alcohol abuse interfering with normal functioning in the period of one year prior to study onset.
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.

Name	Affiliation	Role
Matthew BB McCall, MD, PhD	Radboud University Medical Center	Principal Investigator

Facility	Status	City	State	ZIP	Country	Contacts
Radboud University Medical Center		Nijmegen	Gelderland	6525 GA	Netherlands

PubMed Identifier	Type	Citation	Retractions
35963275	Derived	van der Boor SC, Smit MJ, van Beek SW, Ramjith J, Teelen K, van de Vegte-Bolmer M, van Gemert GJ, Pickkers P, Wu Y, Locke E, Lee SM, Aponte J, King CR, Birkett AJ, Miura K, Ayorinde MA, Sauerwein RW, Ter Heine R, Ockenhouse CF, Bousema T, Jore MM, McCall MBB. Safety, tolerability, and Plasmodium falciparum transmission-reducing activity of monoclonal antibody TB31F: a single-centre, open-label, first-in-human, dose-escalation, phase 1 trial in healthy malaria-naive adults. Lancet Infect Dis. 2022 Nov;22(11):1596-1605. doi: 10.1016/S1473-3099(22)00428-5. Epub 2022 Aug 10.

Arm/Group Information

ID	Title	Description
FG000	Group 1 - 0,1mg/kg TB31F	0.1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. Subjects will be observed for the occurrence of any adverse events. There will be a minimum of 48 hours between TB31F administration to each subsequent volunteer. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising. TB31F: Monoclonal antibody
FG001	Group 2 - 1mg/kg TB31F	1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising. TB31F: Monoclonal antibody
FG002	Group 3 - 3mg/kg TB31F	3 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising. TB31F: Monoclonal antibody
FG003	Group 4 - 10mg/kg TB31F	10 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. TB31F: Monoclonal antibody
FG004	Group 5 - 100mg TB31F	100mg of monoclonal antibody TB31F is administered subcutaneously to 5 subjects. TB31F administration will be staggered such that the first subject will be administered mAb TB31F and observed for the occurrence of any adverse events. The second subject will not receive their dose of TB31F sooner than 2 days after the first subject has received TB31F. The remaining three subjects will receive their TB31F dose no sooner than 2 days after the second subject has been administered TB31F, with at least a one hour interval in administration of TB31F between each subject. Subjects will be followed-up for 84 days. TB31F: Monoclonal antibody

ID	Title	Description
BG000	Group 1 - 0,1mg/kg TB31F	0.1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. Subjects will be observed for the occurrence of any adverse events. There will be a minimum of 48 hours between TB31F administration to each subsequent volunteer. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising. TB31F: Monoclonal antibody

Units	Counts
Participants	BG000

Title	Description	Population Description	Parameter Type	Dispersion Type	Unit of Measure	Calculate Percentage	Denominator Units Selected	Denominators	Classes
Age, Continuous			Mean

Outcome Measures Module

Outcome Measures

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number and Severity of Adverse Events After TB31F Administration

Number and severity of solicited local adverse events of all severities from first product administration through day 7;
Number and severity of solicited general adverse events and clinically significant hematological and biochemical laboratory abnormalities from first product administration through day 28;
Number and severity of unsolicited adverse events from first product administration through end of study;
Occurrence of serious adverse events from first product administration through end of study

Number of volunteers that experienced a grade 1, 2 or 3 local solicited, general solicited, unsolicited or laboratory adverse event per group.

Posted

Count of Participants

Participants

Throughout study: solicited local adverse events (day 0 - day 7); solicited general adverse events and clinically significant laboratory abnormalities (day 0 - day 28); unsolicited adverse events (day 0 - day 84), serious adverse events (day 0 - day 84)

ID	Title	Description
OG000

Adverse Events Module

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Group 1 - 0,1mg/kg TB31F	0.1 mg/kg of monoclonal antibody TB31F is administered intravenously to 5 subjects. Subjects will be observed for the occurrence of any adverse events. There will be a minimum of 48 hours between TB31F administration to each subsequent volunteer. Subjects will be followed-up for 84 days. Escalation to the next higher dosage group will be dependent upon no safety signals arising. TB31F: Monoclonal antibody

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 5, 2020	Feb 21, 2022	Prot_001.pdf
SAP	No	Yes	No	Statistical Analysis Plan	Dec 18, 2020	Jan 15, 2021	SAP_000.pdf

ID	Term
D016778	Malaria, Falciparum
D008288	Malaria

ID	Term
D011528	Protozoan Infections
D010272	Parasitic Diseases
D007239	Infections
D000096724	Mosquito-Borne Diseases