Trial to Evaluate L9LS in Healthy Adults

NCT05019729 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 10000536000536-I
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

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.

Conditions

Malaria

Keywords

Malaria Parasitemia; Malaria Challenge; First in Human; Mosquito; Prevention

Outcome Measures

Primary Outcomes (7)

• 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.

  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.

  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.

  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.

  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.

  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.

  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.

  Day 0 through 4 weeks after L9LS product administration

Secondary Outcomes (8)

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

  Up to 21 days after CHMI

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

  Baseline through 24 weeks after L9LS product administration

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

  Baseline through 24 weeks after L9LS product administration

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

  Baseline through 24 weeks after L9LS product administration

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

  Baseline through 24 weeks after L9LS product administration

Study Arms (6)

Group 1: L9LS (1 mg/kg IV)

EXPERIMENTAL

L9LS (1 mg/kg) administered by intravenous (IV) infusion (Day 0)

Drug: VRC-MALMAB0114-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Group 2: L9LS (5 mg/kg IV)

EXPERIMENTAL

L9LS (5 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0114-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Group 3: L9LS (5 mg/kg SC)

EXPERIMENTAL

L9LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0)

Drug: VRC-MALMAB0114-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Group 4: L9LS (20 mg/kg IV)

EXPERIMENTAL

L9LS (20 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0114-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Group 5: CHMI Controls

OTHER

Control participants who did not receive L9LS and were enrolled to complete the controlled human malaria infection (CHMI)

Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Group 6: L9LS (5 mg/kg IM)

EXPERIMENTAL

L9LS (5 mg/kg) administered by intramuscular (IM) injection (Day 0)

Drug: VRC-MALMAB0114-00-AB

Interventions

VRC-MALMAB0114-00-AB DRUG

VRC-MALMAB0114-00-AB (L9LS) is a monoclonal antibody that binds an epitope of the Plasmodium falciparum circumsporozoite protein.

Also known as: L9LS

Group 1: L9LS (1 mg/kg IV); Group 2: L9LS (5 mg/kg IV); Group 3: L9LS (5 mg/kg SC); Group 4: L9LS (20 mg/kg IV); Group 6: L9LS (5 mg/kg IM)

Plasmodium falciparum (P. falciparum) sporozoite challenge OTHER

Participants were exposed to bites on the forearm from mosquitoes infected with Plasmodium falciparum

Group 1: L9LS (1 mg/kg IV); Group 2: L9LS (5 mg/kg IV); Group 3: L9LS (5 mg/kg SC); Group 4: L9LS (20 mg/kg IV); Group 5: CHMI Controls

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• A volunteer must have met all of the following criteria to be included:
• Able and willing to complete the informed consent process
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process
• Available for clinical follow-up through the last study visit
• to 50 years of age
• In good general health without clinically significant medical history
• Physical examination without clinically significant findings within the 56 days prior to enrollment
• Weight \<= 115 kg (except Group 5)
• Adequate venous access if assigned to an IV group or adequate subcutaneous tissue if assigned to an SC group
• Willing to have blood samples collected, stored indefinitely, and used for research purposes
• Agrees to participate in a controlled human malaria infection (CHMI) and to comply with post-CHMI follow-up requirements (except Group 6)
• Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 6)
• 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:
• White Blood Cell (WBC) 2,500-12,000/mm\^3

You may not qualify if:

• A volunteer would have been excluded if one or more of the following conditions applied:
• Woman who is breast-feeding or planning to become pregnant during study participation
• Previous receipt of a malaria vaccine or anti-malaria monoclonal antibody
• History of malaria infection
• 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
• Hypertension that is not well controlled
• Receipt of any live attenuated vaccines within 28 days prior to enrollment/product administration
• Receipt of any vaccine within 2 weeks prior to enrollment/product administration
• 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
• History of a splenectomy, sickle cell disease or sickle cell trait
• History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 6)
• Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 6)
• Use or planned use of any drug with antimalarial activity that would coincide with study product or CHMI (except Group 6)
• History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 6)
• Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Seder RA, Chang LJ, Enama ME, Zephir KL, Sarwar UN, Gordon IJ, Holman LA, James ER, Billingsley PF, Gunasekera A, Richman A, Chakravarty S, Manoj A, Velmurugan S, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, Plummer SH, Hendel CS, Novik L, Costner PJ, Mendoza FH, Saunders JG, Nason MC, Richardson JH, Murphy J, Davidson SA, Richie TL, Sedegah M, Sutamihardja A, Fahle GA, Lyke KE, Laurens MB, Roederer M, Tewari K, Epstein JE, Sim BK, Ledgerwood JE, Graham BS, Hoffman SL; VRC 312 Study Team. Protection against malaria by intravenous immunization with a nonreplicating sporozoite vaccine. Science. 2013 Sep 20;341(6152):1359-65. doi: 10.1126/science.1241800. Epub 2013 Aug 8.

  PMID: 23929949 BACKGROUND

• Ishizuka AS, Lyke KE, DeZure A, Berry AA, Richie TL, Mendoza FH, Enama ME, Gordon IJ, Chang LJ, Sarwar UN, Zephir KL, Holman LA, James ER, Billingsley PF, Gunasekera A, Chakravarty S, Manoj A, Li M, Ruben AJ, Li T, Eappen AG, Stafford RE, K C N, Murshedkar T, DeCederfelt H, Plummer SH, Hendel CS, Novik L, Costner PJ, Saunders JG, Laurens MB, Plowe CV, Flynn B, Whalen WR, Todd JP, Noor J, Rao S, Sierra-Davidson K, Lynn GM, Epstein JE, Kemp MA, Fahle GA, Mikolajczak SA, Fishbaugher M, Sack BK, Kappe SH, Davidson SA, Garver LS, Bjorkstrom NK, Nason MC, Graham BS, Roederer M, Sim BK, Hoffman SL, Ledgerwood JE, Seder RA. Protection against malaria at 1 year and immune correlates following PfSPZ vaccination. Nat Med. 2016 Jun;22(6):614-23. doi: 10.1038/nm.4110. Epub 2016 May 9.

  PMID: 27158907 BACKGROUND

• Gaudinski MR, Berkowitz NM, Idris AH, Coates EE, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Hu Z, Campos Chagas A, O'Connell S, Basappa M, Douek N, Narpala SR, Barry CR, Widge AT, Hicks R, Awan SF, Wu RL, Hickman S, Wycuff D, Stein JA, Case C, Evans BP, Carlton K, Gall JG, Vazquez S, Flach B, Chen GL, Francica JR, Flynn BJ, Kisalu NK, Capparelli EV, McDermott A, Mascola JR, Ledgerwood JE, Seder RA; VRC 612 Study Team. A Monoclonal Antibody for Malaria Prevention. N Engl J Med. 2021 Aug 26;385(9):803-814. doi: 10.1056/NEJMoa2034031. Epub 2021 Aug 11.

  PMID: 34379916 BACKGROUND

• Lyke KE, Berry AA, Mason K, Idris AH, O'Callahan M, Happe M, Strom L, Berkowitz NM, Guech M, Hu Z, Castro M, Basappa M, Wang L, Low K, Holman LA, Mendoza F, Gordon IJ, Plummer SH, Trofymenko O, Strauss KS, Joshi S, Shrestha B, Adams M, Chagas AC, Murphy JR, Stein J, Hickman S, McDougal A, Lin B, Narpala SR, Vazquez S, Serebryannyy L, McDermott A, Gaudinski MR, Capparelli EV, Coates EE, Wu RL, Ledgerwood JE, Dropulic LK, Seder RA; VRC 612 Part C Study Team. Low-dose intravenous and subcutaneous CIS43LS monoclonal antibody for protection against malaria (VRC 612 Part C): a phase 1, adaptive trial. Lancet Infect Dis. 2023 May;23(5):578-588. doi: 10.1016/S1473-3099(22)00793-9. Epub 2023 Jan 25.

  PMID: 36708738 BACKGROUND

• Wu RL, Idris AH, Berkowitz NM, Happe M, Gaudinski MR, Buettner C, Strom L, Awan SF, Holman LA, Mendoza F, Gordon IJ, Hu Z, Campos Chagas A, Wang LT, Da Silva Pereira L, Francica JR, Kisalu NK, Flynn BJ, Shi W, Kong WP, O'Connell S, Plummer SH, Beck A, McDermott A, Narpala SR, Serebryannyy L, Castro M, Silva R, Imam M, Pittman I, Hickman SP, McDougal AJ, Lukoskie AE, Murphy JR, Gall JG, Carlton K, Morgan P, Seo E, Stein JA, Vazquez S, Telscher S, Capparelli EV, Coates EE, Mascola JR, Ledgerwood JE, Dropulic LK, Seder RA; VRC 614 Study Team. Low-Dose Subcutaneous or Intravenous Monoclonal Antibody to Prevent Malaria. N Engl J Med. 2022 Aug 4;387(5):397-407. doi: 10.1056/NEJMoa2203067.

  PMID: 35921449 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Malaria

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases

Results Point of Contact

• Title: VRC Clinical Trials Program Leadership
• Organization: Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health

ctpleadership@mail.nih.gov

301-451-8715

Study Officials

• Richard L Wu, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2021
• First Posted: August 25, 2021
• Study Start: September 13, 2021
• Primary Completion: September 19, 2022
• Study Completion: September 19, 2022
• Last Updated: August 14, 2024
• Results First Posted: October 13, 2023

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)