Trial to Evaluate L9LS in Healthy Adults

Phase 1CompletedNCT05019729

National Institute of Allergy and Infectious Diseases (NIAID)32 enrolled

Overview

Background: Malaria is a parasitic disease carried by mosquitoes in tropical areas. There is no vaccine to prevent malaria infection. If not treated right away, it can become serious or deadly. Researchers want to test a drug to prevent malaria. Objective: To test if the drug L9LS is safe and if it prevents malaria infection in people. Eligibility: Healthy adults ages 18-50 who have never had malaria. Design: Participants were screened with a medical history, physical exam, and blood tests. Participants were divided into 6 groups: * Three groups received L9LS by infusion into a vein, and gave blood samples before and after infusion. * One group received L9LS injected into the fat under the skin. * One group did not get L9LS. * One group received L9LS injected into the muscle. All participants who received L9LS were monitored for side effects. They had 2-3 follow-up visits during the week after the drug was given, and gave blood samples. They received a thermometer to check their temperature daily for 7 days. They received a tool to measure any redness, swelling, or bruising at the injection site. Most participants took part in the controlled human malaria infection (CHMI) or malaria challenge to find out if L9LS prevents malaria after being bitten by infected mosquitos. Participants in the group who received L9LS injected in the muscle were enrolled after CHMI and did not take part in the CHMI. Participants who received CHMI were bitten by mosquitoes carrying the malaria parasites. A cup containing mosquitoes was placed on their arm for 5 minutes. On days 7-17 after exposure, they received daily study visits to give blood samples. Those who got malaria were treated immediately. On day 21, all CHMI participants received treatment for malaria. Participation lasted 2-6 months, depending on study group.

This was a Phase 1, open-label, dose escalation study to evaluate the safety, tolerability, pharmacokinetics and protective efficacy of an anti-malaria human monoclonal antibody, VRC-MALMAB0114-00-AB (L9LS). The primary hypothesis was that L9LS will be safe and well tolerated when administered by either intravenous (IV),subcutaneous (SC) or intramuscular (IM) routes. The secondary objectives were that L9LS will be detectable in human sera with a definable half-life and confer protection following a controlled human malaria infection (CHMI). The study started with enrollment into Group 1. Interim safety evaluations occurred and supported continued evaluation of L9LS prior to enrolling participants into additional dose groups. All L9LS recipients in Groups 1-4 were invited to participate in the CHMI. Group 5 participants did not receive L9LS, in order to serve as the control group for the CHMI. After CHMI, all CHMI participants were evaluated for malaria parasitemia. Participants who developed blood stage infection were treated as soon as identified per protocol criteria. Participants in Group 6 received L9LS but did not take part in the CHMI. Study follow-up continued through 24 weeks post product administration or 8 weeks post- CHMI, whichever was the most stringent. Study Groups: Group 1: 5 participants - 1mg/kg IV + CHMI Group 2: 4 participants - 5 mg/kg IV + CHMI (1 participant declined to participate in the CHMI) Group 3: 5 participants - 5 mg/ kg SC + CHMI Group 4: 4 participants - 20 mg/kg IV + CHMI Group 5: 9 participants - CHMI Controls (No L9LS given; 3 back up participants were not needed so were terminated early and did not participate in the CHMI) Group 6: 5 participants - 5 mg/kg IM

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

INCLUSION CRITERIA: A volunteer must have met all of the following criteria to be included: 1. Able and willing to complete the informed consent process 2. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process 3. Available for clinical follow-up through the last study visit 4. 18 to 50 years of age 5. In good general health without clinically significant medical history 6. Physical examination without clinically significant findings within the 56 days prior to enrollment 7. Weight \<= 115 kg (except Group 5) 8. Adequate venous access if assigned to an IV group or adequate subcutaneous tissue if assigned to an SC group 9. Willing to have blood samples collected, stored indefinitely, and used for research purposes 10. Agrees to participate in a controlled human malaria infection (CHMI) and to comply with post-CHMI follow-up requirements (except Group 6) 11. Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 6) 12. Agrees not to travel to a malaria endemic region during the entire course of study participation (except Group 6) Laboratory Criteria within 56 days prior to enrollment: 13. White Blood Cell (WBC) 2,500-12,000/mm\^3 14. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval 15. Platelets = 125,000-500,000/mm\^3 16. Hemoglobin within institutional normal range or accompanied by the PI or designee approval 17. Creatinine \<= 1.1 x upper limit of normal (ULN) 18. Alanine aminotransferase (ALT) \<=1.25 x ULN 19. Negative for HIV infection by an FDA approved method of detection Laboratory Criteria documented any time during screening, prior to enrollment: 20. Negative polymerase chain reaction (PCR) for malaria (except Group 6) 21. Negative sickle cell screening test (except Group 6) 22. Electrocardiogram (ECG) without clinically significant abnormalities (examples may include: pathologic Q waves, significant ST-T wave changes, left ventricular hypertrophy, any non-sinus rhythm excluding isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block). ECG abnormalities determined by a cardiologist to be clinically insignificant as related to study participation do not preclude study enrollment (except Group 6) 23. No evidence of increased cardiovascular disease risk; defined as \>10% five-year risk by the non-laboratory method (except Group 6) Criteria Specific to Women: 24. Postmenopausal for at least 1 year, post-hysterectomy or bilateral oophorectomy, or if of childbearing potential: 1. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on day of enrollment, and prior to product administration and CHMI, and 2. Agrees to use an effective means of birth control through the duration of study participation EXCLUSION CRITERIA: A volunteer would have been excluded if one or more of the following conditions applied: 1. Woman who is breast-feeding or planning to become pregnant during study participation 2. Previous receipt of a malaria vaccine or anti-malaria monoclonal antibody 3. History of malaria infection 4. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study 5. Hypertension that is not well controlled 6. Receipt of any investigational study product within 28 days prior to enrollment/product administration (Note: SARS-CoV-2 vaccines approved by emergency use authorization are not exclusionary) 7. Receipt of any live attenuated vaccines within 28 days prior to enrollment/product administration 8. Receipt of any vaccine within 2 weeks prior to enrollment/product administration 9. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with intramuscular injections or blood draws 10. History of a splenectomy, sickle cell disease or sickle cell trait 11. History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 6) 12. Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 6) 13. Use or planned use of any drug with antimalarial activity that would coincide with study product or CHMI (except Group 6) 14. History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 6) 15. Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin 16. History of Sjogren's Syndrome 17. History of chronic or recurrent salivary gland disorder diagnosed by a clinician (note: an isolated occurrence of parotitis, sialadenitis, sialolithiasis, or of a salivary gland tumor is not exclusionary) 18. History of therapeutic head or neck radiation 19. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, autoimmune disease, infectious diseases, psychiatric disorders, heart disease, or cancer

Outcomes

Primary Outcomes

Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration

Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.

Time frame: 7 days after L9LS product administration, at approximately Week 1

Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration

Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.

Time frame: 7 days after L9LS product administration, at approximately Week 1

Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following L9LS Product Administration

Unsolicited adverse event (AE) data collection included AEs of all severities from the date of product administration through the Day 28 post-product administration visit. At other time periods between study product administration and when greater than 4 weeks after the study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that required ongoing medical management (reported as a separate outcome) were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

Time frame: Day 0 through 4 weeks after L9LS product administration

Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (CHMI)

Unsolicited adverse event (AE) data collection included AEs of all severities from CHMI through the Day 28 post-CHMI visit. The relationship between an AE and CHMI was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

Time frame: Day 0 through 4 weeks after CHMI

Number of Participants With Serious Adverse Events (SAEs) Following L9LS Product Administration

SAEs were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a SAE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

Time frame: Day 0 after L9LS product administration through the study participation, up to Week 24

Number of Participants With New Chronic Medical Conditions Following L9LS Product Administration

New chronic medical conditions that required ongoing medical management were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a new chronic medical condition and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.

Time frame: Day 0 after L9LS product administration through the study participation, up to Week 24

Number of Participants With Abnormal Laboratory Measures of Safety Following L9LS Product Administration

Abnormal laboratory results recorded as unsolicited adverse events (AEs) are summarized. Safety lab parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV), platelets, and white blood cell (WBC), red blood cell (RBC), neutrophil, lymphocyte, monocyte, eosinophil and basophil counts) and chemistry (Comprehensive Metabolic Panel (CMP) including alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential, CMP and ALT and creatinine results were collected at different timepoints throughout the study per the protocol's schedule of evaluations. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 were used.

Time frame: Day 0 through 4 weeks after L9LS product administration

Secondary Outcomes

Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge

Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine whether IV or SC administration of L9LS mediates protection against infectious P. falciparum following CHMI

Time frame: Up to 21 days after CHMI

Pharmacokinetic (PK) Parameters of L9LS: Maximum Observed Serum Concentration (Cmax)

Serum concentrations of L9LS by dose group following a single administration. Cmax is the peak serum concentration that L9LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group.

Time frame: Baseline through 24 weeks after L9LS product administration

Pharmacokinetic (PK) Parameters of L9LS: Time to Reach Maximum Observed Serum Concentration (Tmax)

Tmax is the time it takes to reach Cmax of L9LS after it has been administered; it is determined based on the summary PK curve for each dose group.

Time frame: Baseline through 24 weeks after L9LS product administration

Pharmacokinetic (PK) Parameters of L9LS: Beta Half-life (T1/2b)

Beta half-life (T1/2b) is being reported for this study. Beta half-life (T1/2b) is the time required for half of the L9LS product to be eliminated from the serum.

Time frame: Baseline through 24 weeks after L9LS product administration

Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL) Following IV Administration

Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each IV group.

Time frame: Baseline through 24 weeks after L9LS product administration

Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL/F) Following SC or IM Administration

Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each SC and IM group. Clearance following a SC or IM administration is calculated as Clearance (CL)/Bioavailability (F).

Trial to Evaluate L9LS in Healthy Adults

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes