Safety, Tolerability, and Pharmacokinetics and Pharmacodynamics of TB31F

Radboud University Medical Center

Status and phase: Completed; Phase 1

Conditions: Malaria,Falciparum

Treatments: Biological: TB31F

Study type: Interventional

Funder types: Other

Identifiers

NCT04238689

NL69779.091.19

Details and patient eligibility

About

This phase 1 study aims to assess the safety and tolerability of monoclonal antibody TB31F administered intravenously or subcutaneously at escalating dose levels in healthy, malaria naïve, adults. This study will also evaluate the pharmacokinetics of TB31F and the functional activity of mAb TB31F in the standard membrane feeding assay.

Full description

This phase 1 study aims to assess the safety and tolerability of monoclonal antibody (mAb) TB31F administered intravenously or subcutaneously in healthy, malaria naïve, adults at the Radboud University Medical Center (Radboudumc). Five groups will receive a single dose of mAb TB31F. Group 1 (n=5) will receive 0.1 mg/kg TB31F, Group 2 (n=5) will receive 1 mg/kg TB31F, group 3 (n=5) will receive 3 mg/kg TB31F, and group 4 (n=5) will receive 10 mg/kg mAb TB31F intravenously. Group 5 will receive 100mg TB31F subcutaneously. Twenty-five (n=25) subjects will be enrolled, as well as 1 reserve subject per group. Safety follow-up will be done at following times: baseline, end of infusion (EOI), 1, 3, 6 and 24 hours and 2, 7, 14, 21, 28, 56 and 84 days after administration. Extra follow-up visits at 4 and 10 days after administration for collection of serum/plasma for pharmacokinetic and pharmacodynamic measurements will be performed in group 5.

Enrollment: 25 patients

Sex: All

Ages: 18 to 35 years old

Volunteers: Accepts Healthy Volunteers

Inclusion criteria

1. Subject must sign written informed consent to participate in the trial.
2. 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).
3. In the opinion of the investigator, the subject can and will comply with the requirements of the protocol.
4. 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).
5. The subject will remain within reasonable travelling distance from the study center from day -1 until day +7 after mAb TB31F infusion.
6. 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.
7. 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).
8. The subject agrees to refrain from blood donation to Sanquin or for other purposes throughout the study period according to current Sanquin guidelines.
9. 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

1. 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.

2. 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. 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.

4. Positive urine toxicology test for cannabis, cocaine or amphetamines at screening or at inclusion.

5. Screening tests positive for Human Immunodeficiency Virus (HIV), active Hepatitis B Virus (HBV), Hepatitis C Virus (HCV).

6. Use of any investigational or non-registered product (drug or vaccine) during the study period other than the study product.

7. Participation in any other clinical study in the 30 days prior to the start of the study or during the study period.

8. Prior receipt of an investigational antimalarial monoclonal antibody.

9. History of adverse reactions to monoclonal antibodies.

10. 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.

11. Any history of malaria, positive serology for P. falciparum, or previous participation in any malaria (vaccine) study or Controlled Human Malaria Infection.

12. Body weight >= 115 kg

13. 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.

14. History of drug or alcohol abuse interfering with normal functioning in the period of one year prior to study onset.

15. 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.

Trial design

Primary purpose: Prevention

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

---

25 participants in 5 patient groups

Group 1 - 0.1mg/kg TB31F

Experimental group

Description:

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.

Treatment:

Biological: TB31F

Group 2 - 1mg/kg TB31F

Experimental group

Description:

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.

Treatment:

Biological: TB31F

Group 3 - 3mg/kg TB31F

Experimental group

Description:

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.

Treatment:

Biological: TB31F

Group 4 - 10mg/kg TB31F

Experimental group

Description:

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.

Treatment:

Biological: TB31F

Group 5 - 100mg TB31F

Experimental group

Description:

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.

Treatment:

Biological: TB31F