Trial to Evaluate CIS43LS in Healthy Adults

NCT04206332 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 20001720-I-0017
• Study Type: interventional
• Target: 71
• Locations: 1 country
• Sites: 2

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 the safety and effectiveness of a drug called CIS43LS that could prevent malaria infection. Eligibility: Healthy people ages 18-50 who have never been infected with malaria Design: Participants were enrolled on the basis of eligibility criteria, evaluated by clinical laboratory tests, self-reported medical history, and physical examination. Participants received CIS43LS either infused into a vein in their arm or injected into the fat under the skin. They were monitored for side effects for up to 4 hours after they received the drug. Participants received a thermometer and recorded their temperature and symptoms every day on/with/via a diary card for 7 days after administration. The administration site was checked for redness, swelling, itching or bruising. Participants had up to 12 follow-up visits. At follow-up visits, participants had blood drawn and were checked for health changes or problems. Most participants who received CIS43LS took part in a Controlled Human Malaria Infection Challenge (CHMI) along with control participants who did not receive CIS43LS. During the CHMI, mosquitoes carrying the malaria parasite bit participants in a controlled setting. The participants had clinic visits every day for up to 12 days starting 7 days after the CHMI. Participants were treated right away with antimalarial medication if they tested positive for malaria. Approximately 21 days after the CHMI, participants were treated with antimalarial medication for 3 days. The study lasted 2-6 months depending on the participant's study group.

Conditions

Malaria

Keywords

Prevention and Control; Mosquito; Malaria Challenge; Parasitemia; Passive Immunization; Controlled Human Malaria Infection (CHMI)

Outcome Measures

Primary Outcomes (7)

• Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS 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 CIS43LS product administration, at approximately Week 1

• Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS 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 CIS43LS product administration, at approximately Week 1

• Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following CIS43LS 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 CIS43LS 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 CIS43LS 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 CIS43LS product administration through the study participation, up to Week 24

• Number of Participants With New Chronic Medical Conditions Following CIS43LS 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 CIS43LS product administration through the study participation, up to Week 24

• Number of Participants With Abnormal Laboratory Measures of Safety Following CIS43LS 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 (alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential and Chemistry (ALT and creatinine) results were collected at different timepoints in Parts A, B and C 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 CIS43LS product administration

Secondary Outcomes (10)

• Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part A and Part B)

  Baseline through 24 weeks after CIS43LS product administration

• Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part C)

  Baseline through 24 weeks after CIS43LS product administration

• Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part A and Part B)

  Baseline through 24 weeks after CIS43LS product administration

• Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part C)

  Baseline through 24 weeks after CIS43LS product administration

• Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part A and Part B)

  Baseline through 24 weeks after CIS43LS product administration

Study Arms (17)

Part A, Group 1: CIS43LS (5 mg/kg IV)

EXPERIMENTAL

CIS43LS (5 mg/kg) administered by intravenous (IV) infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB

Part A, Group 2: CIS43LS (5 mg/kg SC)

EXPERIMENTAL

CIS43LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0)

Drug: VRC-MALMAB0100-00-AB

Part A, Group 3: CIS43LS (20 mg/kg IV)

EXPERIMENTAL

CIS43LS (20 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB

Part A, Group 4A: CIS43LS (40 mg/kg IV)

EXPERIMENTAL

CIS43LS (40 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB

Part A, Group 4B: CIS43LS (40 mg/kg IV)

EXPERIMENTAL

CIS43LS (40 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB

Part A, Group 5: CHMI Controls

NO INTERVENTION

Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI); however, Group 5 did not undergo CHMI because of restrictions related to coronavirus disease 2019 (COVID-19)

Part B, Group 6: CIS43LS (5 mg/kg SC)

EXPERIMENTAL

CIS43LS (5 mg/kg) administered by SC injection (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part B, Group 7: CIS43LS (20 mg/kg IV)

EXPERIMENTAL

CIS43LS (20 mg/kg) administered by IV infusion (Day 0) Part B, Group 7 participants included participants previously enrolled in Part A who received either 5 mg/kg IV (1), 5 mg/kg SC (1) or 20 mg/kg IV (2) in the first part of the study and newly enrolled Part B participants

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part B, Group 8: CHMI [CIS43LS (40 mg/kg IV) in Part A]

OTHER

Part B, Group 8 participants included participants previously enrolled in Part A who received CIS43LS (40 mg/kg IV) in the first part of the study but did not receive CIS43LS in Part B of the study. Group 8 participants were enrolled to complete the controlled human malaria infection (CHMI).

Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part B, Group 9: CIS43LS (40 mg/kg IV)

EXPERIMENTAL

CIS43LS (40 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part B, Group 10: CHMI Controls

OTHER

Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI)

Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 11: CIS43LS (1 mg/kg IV)

EXPERIMENTAL

CIS43LS (1 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 12: CIS43LS (5 mg/kg IV)

EXPERIMENTAL

CIS43LS (5 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 13: CIS43LS (5 mg/kg SC)

EXPERIMENTAL

CIS43LS (5 mg/kg) administered by SC injection (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 14: CIS43LS (10 mg/kg IV)

EXPERIMENTAL

CIS43LS (10 mg/kg) administered by IV infusion (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 15: CIS43LS (10 mg/kg SC)

EXPERIMENTAL

CIS43LS (10 mg/kg) administered by SC injection (Day 0)

Drug: VRC-MALMAB0100-00-AB; Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Part C, Group 16: CHMI Controls

OTHER

Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI)

Other: Plasmodium falciparum (P. falciparum) sporozoite challenge

Interventions

VRC-MALMAB0100-00-AB DRUG

VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.

Also known as: CIS43LS

Part A, Group 1: CIS43LS (5 mg/kg IV); Part A, Group 2: CIS43LS (5 mg/kg SC); Part A, Group 3: CIS43LS (20 mg/kg IV); Part A, Group 4A: CIS43LS (40 mg/kg IV); Part A, Group 4B: CIS43LS (40 mg/kg IV); Part B, Group 6: CIS43LS (5 mg/kg SC); Part B, Group 7: CIS43LS (20 mg/kg IV); Part B, Group 9: CIS43LS (40 mg/kg IV); Part C, Group 11: CIS43LS (1 mg/kg IV); Part C, Group 12: CIS43LS (5 mg/kg IV); Part C, Group 13: CIS43LS (5 mg/kg SC); Part C, Group 14: CIS43LS (10 mg/kg IV); Part C, Group 15: CIS43LS (10 mg/kg SC)

Plasmodium falciparum (P. falciparum) sporozoite challenge OTHER

Participants were exposed to bites on the forearm from Anopheles stephensi mosquitoes infected with P. falciparum (3D7 strain).

Part B, Group 10: CHMI Controls; Part B, Group 6: CIS43LS (5 mg/kg SC); Part B, Group 7: CIS43LS (20 mg/kg IV); Part B, Group 8: CHMI [CIS43LS (40 mg/kg IV) in Part A]; Part B, Group 9: CIS43LS (40 mg/kg IV); Part C, Group 11: CIS43LS (1 mg/kg IV); Part C, Group 12: CIS43LS (5 mg/kg IV); Part C, Group 13: CIS43LS (5 mg/kg SC); Part C, Group 14: CIS43LS (10 mg/kg IV); Part C, Group 15: CIS43LS (10 mg/kg SC); Part C, Group 16: CHMI Controls

Eligibility Criteria

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

You may qualify if:

• 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 (for all groups except Groups 5, 10, and 16) and \< 100 kg for Group 15
• 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 4B)
• Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 4B)
• Agrees not to travel to a malaria endemic region during the entire course of study participation
• Laboratory Criteria within 56 days prior to enrollment:
• White Blood Cell (WBC) 2,500-12,000/mm\^3
• WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval

You may not qualify if:

• Woman who is breast-feeding or planning to become pregnant during study participation
• Previous receipt of a malaria vaccine
• History of malaria infection
• History of severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defined per FDA guidance
• Active SARS-CoV-2 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
• 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 4B)
• Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 4B)
• Use or planned use of any drug, including antibiotics, with antimalarial activity within 4 weeks prior to CHMI
• History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 4B)
• 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)

Sponsors & Collaborators

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

Study Sites (2)

University of Maryland Baltimore, Center for Vaccine Development

Baltimore, Maryland, 21201-1595, United States

Location

VRC Clinic, NIH Clinical Center

Bethesda, Maryland, 20814, United States

Location

Related Publications (6)

• 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.

  PMID: 30686586 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

• 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

• Kayentao K, Ongoiba A, Preston AC, Healy SA, Doumbo S, Doumtabe D, Traore A, Traore H, Djiguiba A, Li S, Peterson ME, Telscher S, Idris AH, Kisalu NK, Carlton K, Serebryannyy L, Narpala S, McDermott AB, Gaudinski M, Traore S, Cisse H, Keita M, Skinner J, Hu Z, Zeguime A, Ouattara A, Doucoure M, Dolo A, Djimde A, Traore B, Seder RA, Crompton PD; Mali Malaria mAb Trial Team. Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali. N Engl J Med. 2022 Nov 17;387(20):1833-1842. doi: 10.1056/NEJMoa2206966. Epub 2022 Oct 31.

  PMID: 36317783 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 RESULT

• 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 RESULT

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Malaria; Parasitemia

Interventions

CIS43LS

Condition Hierarchy (Ancestors)

Protozoan Infections; Parasitic Diseases; Infections; Mosquito-Borne Diseases; Vector Borne Diseases; Sepsis; Systemic Inflammatory Response Syndrome; Inflammation; Pathologic Processes; Pathological Conditions, Signs and Symptoms

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

• Clinical Trials Program Leadership:ctpleadership@mail.nih.gov

  VRC, National Institute of Allergy and Infectious Diseases, National Institutes of Health

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

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: December 19, 2019
• First Posted: December 20, 2019
• Study Start: January 7, 2020
• Primary Completion: February 28, 2022
• Study Completion: February 28, 2022
• Last Updated: April 18, 2023
• Results First Posted: April 18, 2023

Record last verified: 2023-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)