Trial to Evaluate L9LS in Healthy Adults
- Conditions
- Malaria
- Interventions
- Drug: VRC-MALMAB0114-00-ABOther: Plasmodium falciparum (P. falciparum) sporozoite challenge
- Registration Number
- NCT05019729
- Brief Summary
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.
- Detailed Description
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
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 32
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Group 1: L9LS (1 mg/kg IV) VRC-MALMAB0114-00-AB L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) Group 1: L9LS (1 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0) Group 3: L9LS (5 mg/kg SC) VRC-MALMAB0114-00-AB L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) Group 2: L9LS (5 mg/kg IV) VRC-MALMAB0114-00-AB L9LS (5 mg/kg) administered by IV infusion (Day 0) Group 2: L9LS (5 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge L9LS (5 mg/kg) administered by IV infusion (Day 0) Group 3: L9LS (5 mg/kg SC) Plasmodium falciparum (P. falciparum) sporozoite challenge L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) Group 4: L9LS (20 mg/kg IV) VRC-MALMAB0114-00-AB L9LS (20 mg/kg) administered by IV infusion (Day 0) Group 4: L9LS (20 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge L9LS (20 mg/kg) administered by IV infusion (Day 0) Group 5: CHMI Controls Plasmodium falciparum (P. falciparum) sporozoite challenge Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI) Group 6: L9LS (5 mg/kg IM) VRC-MALMAB0114-00-AB L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0)
- Primary Outcome Measures
Name Time Method Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration 7 days after L9LS product administration, at approximately Week 1 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.
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following L9LS Product Administration Day 0 through 4 weeks after 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.
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (CHMI) Day 0 through 4 weeks after 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.
Number of Participants With Serious Adverse Events (SAEs) Following L9LS Product Administration Day 0 after L9LS product administration through the study participation, up to Week 24 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.
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration 7 days after L9LS product administration, at approximately Week 1 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.
Number of Participants With New Chronic Medical Conditions Following L9LS Product Administration Day 0 after L9LS product administration through the study participation, up to Week 24 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.
Number of Participants With Abnormal Laboratory Measures of Safety Following L9LS Product Administration Day 0 through 4 weeks after 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.
- Secondary Outcome Measures
Name Time Method Pharmacokinetic (PK) Parameters of L9LS: Maximum Observed Serum Concentration (Cmax) Baseline through 24 weeks after L9LS product administration 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.
Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL) Following IV Administration Baseline through 24 weeks after L9LS product administration Rate of L9LS elimination divided by the plasma L9LS concentration; determined based on the summary pharmacokinetic (PK) curve for each IV group.
Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss) Following IV Administration Baseline through 24 weeks after L9LS product administration Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the pharmacokinetic (PK) curve for each IV group.
Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss/F) Following SC or IM Administration Baseline through 24 weeks after L9LS product administration Theoretical volume that would be necessary to contain the total amount of administered drug at the same concentration as observed in plasma. It represents the degree to which a drug is distributed in body tissue rather than the plasma and calculated based in the PK curve for each SC and IM group. Volume of distribution at steady-state (Vss) following a SC or IM administration is calculated as Volume of distribution at steady-state (Vss)/Bioavailability (F).
Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge Up to 21 days after CHMI 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
Pharmacokinetic (PK) Parameters of L9LS: Time to Reach Maximum Observed Serum Concentration (Tmax) Baseline through 24 weeks after L9LS product administration 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.
Pharmacokinetic (PK) Parameters of L9LS: Beta Half-life (T1/2b) Baseline through 24 weeks after L9LS product administration 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.
Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL/F) Following SC or IM Administration Baseline through 24 weeks after L9LS product 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 Locations
- Locations (1)
National Institutes of Health Clinical Center
🇺🇸Bethesda, Maryland, United States