Trial to Evaluate CIS43LS in Healthy Adults

• ClinicalTrials.gov Identifier: NCT04206332
• Recruitment Status: Completed
• First Posted: December 20, 2019
• Last Update Posted: November 14, 2022
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

Brief Summary:

Background:

People get malaria when they are bitten by an infected mosquito. Malaria can be serious and sometimes deadly. Although there are medicines to treat malaria, there is no vaccine that fully prevents infection. Researchers want to test if an experimental drug can help.

Objective:

To test a drug called CIS43LS that could prevent malaria infection.

Eligibility:

Healthy people ages 18-50 who have never been infected with malaria

Design:

Participants will be screened with a physical exam, blood tests, and medical history.

Some participants will get pregnancy tests.

Most participants will get CIS43LS. They will get the drug infused into a vein in their arm or injected into the fat under the skin. They will be monitored for side effects for up to 4 hours after they get the drug.

Participants will be given a thermometer to check their temperature every day for 7 days. They will also be given a device to measure any redness, swelling, or bruising at the injection site.

Participants will have up to 12 follow-up visits. These will include blood tests.

Most participants will take part in a Controlled Human Malaria Challenge (CHMI). During the CHMI, mosquitoes carrying the malaria parasite will bite participants in a controlled setting. The participants will then have clinic visits every day for up to 12 days starting 7 days after the CHMI. They will be treated right away with antimalarial medication if the test shows positive for malaria. If participants continue to test negative for malaria, they will have 2 more visits over the next 6 days for blood tests. Then 28 days after the CHMI they will get treated with antimalarial medication for 3 days. The study will last 2-6 months depending on participants study group....

Condition or disease	Intervention/treatment	Phase
Malaria	Drug: VRC-MALMAB0100-00-AB; Other: CHMI	Phase 1

Detailed Description:

This is a Phase 1, open-label, dose escalation study to evaluate the dose, safety, tolerability and protective efficacy of an anti-malaria human monoclonal antibody, VRC-MALMAB0100-00-AB (CIS43LS). The primary hypothesis is to evaluate the safety and tolerability of CIS43LS when administered by either intravenous (IV) or subcutaneous (SC) routes. The secondary objectives are that CIS43LS will be detectable in human sera with a definable half-life and will confer protection following a controlled human malaria infection (CHMI).

Part A: Part A evaluated the doses and routes as shown below in the Study Schema table in an open-label, dose escalation design.

Part B: Part B evaluated CIS43LS doses and routes prior to CHMI in Part A veteran subjects and new Part B enrollees.

Part C: Part C will evaluate CIS43LS doses and routes needed to reach a threshold of protection by assessing serum concentration prior to CHMI in a dose down design.

Enrollment of up to 100 healthy subjects, 18-50 years of age, who are malaria-naive is permitted. All subjects who receive CIS43LS will be followed for 24 weeks after product administration. Control subjects will be followed through 8 weeks after CHMI.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 71 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: VRC 612: 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-MALMAB0100-00-AB (CIS43LS), in Healthy, Malaria-Naive Adults
• Actual Study Start Date: January 7, 2020
• Actual Primary Completion Date: February 28, 2022
• Actual Study Completion Date: April 6, 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: Group 1; 5 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Group 10; Control	Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 11; 1 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 12; 5 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 13; 5 mg/kg SC	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 14; 10 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 15; 10 mg/kg SC	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Group 16; Control	Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 2; 5 mg/kg SC	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 3; 20 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 4a; 40 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 4b; 40 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 5; Control	Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 6; 5 mg/kg SC	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 7; 20 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Group 8; No additional study product	Other: CHMI; Negative control designed to test the infection ability of the CHMI.
Experimental: Group 9; 40 mg/kg IV	Drug: VRC-MALMAB0100-00-AB; VRC-MALMAB0100-00-AB is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum circumsporozoite protein. The monoclonal antibody was adapted resulting in an LS mutation found to increase product half-life in plasma.; Other: CHMI; Negative control designed to test the infection ability of the CHMI.

Outcome Measures

Primary Outcome Measures :

1. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   1 mg/kg IV of CIS43LS will be administered to healthy, malaria-naive adults.
2. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   10 mg/kg SC of CIS43LS will be administered to healthy, malaria-naive adults.
3. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   5 mg/kg IV of CIS43LS will be administered to healthy, malaria-naive adults.
4. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   5 mg/kg SC of CIS43LS will be administered to healthy, malaria-naive adults.
5. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   20 mg/kg IV of CIS43LS will be administered to healthy, malaria-naive adults.
6. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   10 mg/kg IV of CIS43LS will be administered to healthy, malaria-naive adults.
7. To evaluate the safety and tolerability of CIS43LS [ Time Frame: Through 24 weeks after product administration ]
   40 mg/kg IV of CIS43LS will be administered to healthy, malaria-naive adults.

Secondary Outcome Measures :

1. To determine if CIS43LS confers protection [ Time Frame: Following CHMI ]
   To determine if the administration of CIS43LS confers protection against plasmodium falciparum following CHMI.
2. To evaluate the pharmacokinetics of CIS43LS at each dose level [ Time Frame: Throughout the study ]
   The pharmocokinetics of CIS43LS administered at each dose level will be evaluated.
3. To estimate the lowest dose of CIS43LS administered IV and SC [ Time Frame: Following CHMI ]
   To estimate the lowest dose that confers protection against plasmodium falciparum following CHMI.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

• INCLUSION CRITERIA:

A subject must meet 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 (for all groups except Groups 5, 10, and 16) and < 100 kg for Group 15
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 4B)
11. Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 4B)

12. Agrees not to travel to a malaria endemic region during the entire course of study participation

    Laboratory Criteria within 56 days prior to enrollment:

13. 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 - 400,000/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 prior to enrollment:

20. Negative sickle cell screening test
21. Negative troponin test (except Group 4B)
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 4B)

23. No evidence of increased cardiovascular disease risk; defined as >10% five-year risk by the non-laboratory method (except Group 4B)

    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 subject will be excluded if one or more of the following conditions apply:

1. Woman who is breast-feeding or planning to become pregnant during study participation
2. Previous receipt of a malaria vaccine
3. History of malaria infection
4. History of severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defined per FDA guidance
5. Active SARS-CoV-2 infection
6. 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
7. Hypertension that is not well controlled
8. Receipt of any investigational study product within 28 days prior to enrollment (note: Emergency Use Authorization COVID-19 vaccine is not exclusionary)
9. Receipt of any live attenuated vaccines within 28 days prior to enrollment
10. 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
11. History of a splenectomy, sickle cell disease or sickle cell trait
12. History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 4B)
13. Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 4B)
14. Use or planned use of any drug, including antibiotics, with antimalarial activity within 4 weeks prior to CHMI
15. History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 4B)
16. Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin (except Group 4B)
17. 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, psychiatric disorders, heart disease, or cancer

Contacts and Locations

Locations

United States, Maryland

University of Maryland Baltimore, Center for Vaccine Development

Baltimore, Maryland, United States, 21201-1595

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Martin R Gaudinski, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Study Protocol and Statistical Analysis Plan  [PDF] October 26, 2021

Informed Consent Form  [PDF] October 27, 2021

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications:

Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE; VRC 608 Study team. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019 Mar 2;393(10174):889-898. doi: 10.1016/S0140-6736(19)30036-4. Epub 2019 Jan 24. Erratum In: Lancet. 2020 May 30;395(10238):1694.

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. Erratum In: Nat Med. 2016 Jun 7;22(6):692.

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.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT04206332
• Other Study ID Numbers: 200017; 20-I-0017
• First Posted: December 20, 2019
• Last Update Posted: November 14, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No
• Plan Description: .IPD is not shared because it has limited value in a small phase 1 trial of healthy volunteers. We instead report non-IPD data as required in clinicaltrials.gov.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Prevention and Control; Mosquito; Malaria Challenge; Parasitemia; Passive Immunization

Additional relevant MeSH terms:

Malaria; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases