Clinical trial NCT05019729: Trial to Evaluate L9LS in Healthy Adults
Official title: VRC 614: A Phase 1, Dose Escalation, Open-Label Clinical Trial With Experimental Controlled Human Malaria Infections (CHMI) to Evaluate Safety and Protective Efficacy of an Anti-Malaria Human Monoclonal Antibody, VRC-MALMAB0114-00-AB (L9LS), in Healthy Malaria-Naive Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Malaria
Keywords: Malaria Parasitemia
Malaria Challenge
First in Human
Mosquito
Prevention
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2021-08-25
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: PREVENTION

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

Eligibility criteria: 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

Primary outcomes:
measure: Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration
timeFrame: 7 days after L9LS product administration, at approximately Week 1
measure: Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of L9LS Product Administration
timeFrame: 7 days after L9LS product administration, at approximately Week 1
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following L9LS Product Administration
timeFrame: Day 0 through 4 weeks after L9LS product administration
measure: Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (CHMI)
timeFrame: Day 0 through 4 weeks after CHMI
measure: Number of Participants With Serious Adverse Events (SAEs) Following L9LS Product Administration
timeFrame: Day 0 after L9LS product administration through the study participation, up to Week 24
measure: Number of Participants With New Chronic Medical Conditions Following L9LS Product Administration
timeFrame: Day 0 after L9LS product administration through the study participation, up to Week 24
measure: Number of Participants With Abnormal Laboratory Measures of Safety Following L9LS Product Administration
timeFrame: Day 0 through 4 weeks after L9LS product administration
Secondary outcomes:
measure: Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge
timeFrame: Up to 21 days after CHMI
measure: Pharmacokinetic (PK) Parameters of L9LS: Maximum Observed Serum Concentration (Cmax)
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Time to Reach Maximum Observed Serum Concentration (Tmax)
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Beta Half-life (T1/2b)
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL) Following IV Administration
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Clearance (CL/F) Following SC or IM Administration
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss) Following IV Administration
timeFrame: Baseline through 24 weeks after L9LS product administration
measure: Pharmacokinetic (PK) Parameters of L9LS: Volume of Distribution at Steady-State (Vss/F) Following SC or IM Administration
timeFrame: Baseline through 24 weeks after L9LS product administration
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Richard L Wu, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.