Safety and Efficacy of CIS43LS Anti-malaria mAb in Mali

Safety and Efficacy of VRC-MALMAB0100-00-AB (CIS43LS), a Human Monoclonal Antibody Against Plasmodium Falciparum, in a Dose-Escalation Trial and a Randomized, Double-Blind Trial of Adults in Mali

The purpose of this study is to evaluate the safety, tolerability, and efficacy of VRC MALMAB0100-00-AB (CIS43LS), a human monoclonal antibody, against naturally occurring Plasmodium falciparum (Pf) infection.

Study Overview

• Status: Completed
• Conditions: Malaria; Plasmodium Falciparum Infection
• Intervention / Treatment: Biological: VRC-MALMAB0100-00-AB (CIS43LS); Other: Normal saline

Detailed Description

This study will evaluate the safety, tolerability, and efficacy of VRC MALMAB0100-00-AB (CIS43LS), a human monoclonal antibody, against naturally occurring Plasmodium falciparum (Pf) infection.

The first part of the study is an open-label dose-escalation study for safety and tolerability. Participants will be assigned to one of three dose arms. Dosing will begin in the lowest dose arm. Once all participants in that arm reach Day 7 post-infusion, if no safety concerns have arisen, dosing will begin at the subsequent dose level. This process will be repeated until participants complete the third dose arm. Participants will be followed for safety to assess adverse events (AEs) at study visits 1, 3, 7, 14, 21, and 28 days after administration, then monthly through 24 weeks after administration.

After the last subject in the highest dose arm reaches Day 7 safety follow-up, an interim safety evaluation will be performed before enrollment begins for the second part of the study.

The second part of the study is a randomized, double-blind, placebo-controlled trial to assess safety and protective efficacy of CIS43LS and placebo. Participants in the efficacy study will receive the study agent and be followed at study visits 1, 3, 7, 14, 21, and 28 days later, and once every 2 weeks thereafter through 24 weeks. Primary study assessments include physical examinations and blood collection for identification of Pf infection and other research laboratory evaluations.

• Study Type: Interventional
• Enrollment (Actual): 348
• Phase: Phase 2

Contacts and Locations

Study Locations

• Mali
  • Région De Koulikoro
    • Kalifabougou, Région De Koulikoro, Mali
      • Kalifabougou MRTC Clinic
    • Torodo, Région De Koulikoro, Mali
      • Torodo MRTC Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Aged ≥18 and ≤55 years.
• Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
• In good general health and without clinically significant medical history.
• Able to provide informed consent.
• Willing to have blood samples and data stored for future research.
• Resides in or near Kalifabougou or Torodo, Mali, and available for the duration of the study.

• Females of childbearing potential must be willing to use reliable contraception from 21 days prior to study day 0 through the final study visit as described below.

  • Reliable methods of birth control include 1 of the following: confirmed pharmacologic contraceptives via parenteral delivery or intrauterine or implantable device.
  • Nonchildbearing women will be required to report date of last menstrual period, history of surgical sterility (i.e., tubal ligation, hysterectomy) or premature ovarian insufficiency, and will have urine or serum pregnancy test performed per protocol.

Exclusion Criteria:

• Pregnancy, as determined by a positive urine or serum beta-human choriogonadotropin (β-hCG) test (if female).
• Currently breastfeeding.
• Behavioral, cognitive, or psychiatric disease that in the opinion of the investigator affects the ability of the subject to understand and comply with the study protocol.
• Study comprehension examination score of <80% correct or per investigator discretion.
• Hemoglobin, white blood cell, absolute neutrophil, or platelet count outside the local laboratory-defined limits of normal. (Subjects may be included at the investigator's discretion for "not clinically significant" values.)
• Alanine transaminase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Subjects may be included at the investigator's discretion for "not clinically significant" values.)
• Infected with human immunodeficiency virus (HIV), hepatitis C virus (HCV), or hepatitis B virus (HBV).
• Known or documented sickle cell disease by history. (Note: Known sickle cell trait is NOT exclusionary.)
• Clinically significant abnormal electrocardiogram (ECG; corrected QT interval [QTc] >460 or other significant abnormal findings, including unexplained tachycardia or bradycardia).
• Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies including urinalysis.
• Receipt of any investigational product within the past 30 days.
• Participation or planned participation in an interventional trial with an investigational product until the last required protocol visit. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.)
• Medical, occupational, or family problems as a result of alcohol or illicit drug use during the past 12 months.
• History of a severe allergic reaction or anaphylaxis.
• Severe asthma (defined as asthma that is unstable or required emergent care, urgent care, hospitalization, or intubation during the past 2 years, or that has required the use of oral or parenteral corticosteroids at any time during the past 2 years).
• Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjögren's syndrome, or autoimmune thrombocytopenia.
• Known immunodeficiency syndrome.
• Known asplenia or functional asplenia.
• Use of chronic (≥14 days) oral or IV corticosteroids (excluding topical or nasal) at immunosuppressive doses (i.e., prednisone >10 mg/day) or immunosuppressive drugs within 30 days of day 0.
• Receipt of a live vaccine within the past 4 weeks or a killed vaccine within the past 2 weeks prior to study agent administration.
• Receipt of immunoglobulins and/or blood products within the past 6 months.
• Previous receipt of an investigational malaria vaccine in the last 5 years.
• Known allergies or contraindication against artemether-lumefantrine.
• Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of a subject participating in the trial, interfere with the evaluation of the study objectives, or render the subject unable to comply with the protocol.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Sequential Assignment
• Masking: Double

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose-escalation study: Arm 1: 5 mg/kg of CIS43LS; Participants receive 5 mg/kg of CIS43LS as one time intravenous infusion on Day 0.	Biological: VRC-MALMAB0100-00-AB (CIS43LS); Administered via one-time intravenous infusion
Experimental: Dose-escalation study: Arm 2: 10 mg/kg of CIS43LS; Participants receive 10 mg/kg of CIS43LS as one time intravenous infusion on Day 0.	Biological: VRC-MALMAB0100-00-AB (CIS43LS); Administered via one-time intravenous infusion
Experimental: Dose-escalation study: Arm 3: 40 mg/kg of CIS43LS; Participants receive 40 mg/kg of CIS43LS as one time intravenous infusion on Day 0.	Biological: VRC-MALMAB0100-00-AB (CIS43LS); Administered via one-time intravenous infusion
Experimental: Efficacy study: Arm 1: 10 mg/kg of CIS43LS; Participants receive 10 mg/kg of CIS43LS as one time intravenous infusion on Day 0.	Biological: VRC-MALMAB0100-00-AB (CIS43LS); Administered via one-time intravenous infusion
Experimental: Efficacy study: Arm 2: 40 mg/kg of CIS43LS; Participants receive 40 mg/kg of CIS43LS as one time intravenous infusion on Day 0.	Biological: VRC-MALMAB0100-00-AB (CIS43LS); Administered via one-time intravenous infusion
Placebo Comparator: Efficacy study: Arm 3: Placebo; Participants receive placebo as one time intravenous infusion on Day 0.	Other: Normal saline; Administered via one-time intravenous infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Local Adverse Events (AEs)	Participants with incidence of local adverse events occurring within 7 days after administration of CIS43LS. Local reactogenicity included pain/tenderness, swelling, redness, bruising, and pruritus at the site of infusion.	Within 7 days after administration of CIS43LS
Severity of Local Adverse Events (AEs)	The severity of local AEs was graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Clinical Trials. Grade 1: Pain = does not interfere with activity; Tenderness = mild discomfort to touch; Erythema/Redness = 2.5-5 cm; Induration/Swelling = 2.5-5 cm and does not interfere with activity. Grade 2: Pain = Repeated use of non-narcotic pain reliever > 24 hours or interferes with daily activity; Tenderness = Discomfort with movement; Erythema/Redness = 5.1-10 cm; Induration/Swelling = 5.1-10 cm and interferes with activity. Grade 3: Pain = Any use of narcotic pain reliever or prevents daily activity; Tenderness = Significant discomfort at rest; Erythema/Redness = > 10 cm; Induration/Swelling = > 10 cm or prevents daily activity. Grade 4: Pain = Emergency room (ER) visit or hospitalization; Tenderness = ER visit or hospitalization; Erythema/Redness = Necrosis or exfoliative dermatitis; Induration/Swelling = Necrosis Grade 5: Death	Within 7 days after the administration of CIS43LS
Participants With Systemic Adverse Events (AEs)	Participants with incidence of systemic adverse events occurring within 7 days after product administration of CIS43LS. Systemic reactogenicity events included fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint pain.	Within 7 days after the administration of CIS43LS
Severity of Systemic Adverse Events (AEs)	The severity of systemic AEs occurring after the administration of CIS43LS was assessed using the grading scale below: Grade 1: Fever = 37.5^oC-37.9^oC; Fatigue, Headache, Myalgia = No interference with activity; Nausea = no interference with activity or 1-2 episodes/hour Grade 2: Fever = 38^oC-38.4^oC; Fatigue, Myalgia = Some interference with activity; Headache = Repeated use of non-narcotic pain reliever > 24 hours or some interference with activity; Nausea = Some interference with activity or > 2 episodes/24 hours Grade 3: Fever = 38.5^oC-39.5^oC; Fatigue = Prevents daily activity; Headache =Significant; any use of narcotic pain reliever or prevents daily activity; Myalgia =Significant; prevents daily activity; Nausea = Prevents daily activity, requires outpatient intravenous hydration Grade 4: Fever = > 39.5^oC; Fatigue, Headache, Myalgia = Emergency room (ER) visit or hospitalization; Nausea = ER visit or hospitalization for hypotensive shock Grade 5: Death	Within 7 days after the administration of CIS43LS
Participants With Plasmodium Falciparum (Pf) Infection Detected by Microscopic Examination	Number of participants with Plasmodium falciparum (Pf) blood stage infection defined as blood smear-positive for Pf was assessed by microscopic examination of thick blood smear collected from participants from day 7 through week 24 (168 days) after administration of CIS43LS or placebo. Sample was collected every two weeks until week 24.	Day 7 through week 24 (168 days) after administration of intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Plasmodium Falciparum (Pf) Infection Detected by Reverse Transcription Polymerase Chain Reaction (RT-PCR)	Number of participants with Plasmodium falciparum (Pf) blood stage infection defined as blood smear-positive for Pf was assessed by reverse transcription polymerase chain reaction (RT-PCR) using dried blood spot specimen collected from participants from day 21 through week 24 (168 days) after administration of CIS43LS or placebo. Sample was collected every two weeks until 24 weeks. Plasmodium 18S rRNA RT-PCR assay was applied to dried blood spots during analysis.	Day 21 through week 24 (168 days) after administration of intervention
Maximum Serum Concentration (Cmax) for CIS43LS	Maximum serum concentration (Cmax) of CIS43LS by dose group following a single intravenous administration to assess durability of CIS43LS and allow for correlation with Plasmodium falciparum (Pf) infection risk. Cmax is the peak serum concentration that CIS43LS achieves after it has been administered. It is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group and measured by a Meso Scale Discovery LLC-based automation platform.	Measured through Week 24
Time to Maximum Serum Concentration (Tmax) for CIS43LS	Time to maximum total serum concentration (Cmax) of CIS43LS by dose group following a single intravenous administration. Tmax is the time it takes to reach Cmax of CIS43LS after it has been administered; it is determined based on the summary PK curve for each dose group. This was calculated by subtracting the time the CIS43LS intravenous infusion was stopped from the time the blood was collected for the Cmax, at the post-one hour blood draw.	One to 24 hours post-infusion

Collaborators and Investigators

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: University of Washington; Malaria Research and Training Center, Bamako, Mali; Harvard School of Public Health (HSPH)
• Investigators: Principal Investigator: Peter D. Crompton, MD, MPH, National Institutes of Health (NIH); Principal Investigator: Kassoum Kayentao, MD, MPH, PhD, Faculté de Médecine Pharmacie d'Odontostomatologie (FMPOS)

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2021
• Primary Completion (Actual): January 26, 2022
• Study Completion (Actual): July 5, 2023

Study Registration Dates

• First Submitted: March 30, 2020
• First Submitted That Met QC Criteria: March 31, 2020
• First Posted (Actual): April 1, 2020

Study Record Updates

• Last Update Posted (Actual): April 9, 2025
• Last Update Submitted That Met QC Criteria: March 20, 2025
• Last Verified: March 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Vector Borne Diseases; Mosquito-Borne Diseases; Infections; Protozoan Infections; Parasitic Diseases; Malaria
• Other Study ID Numbers: 2020/32/CE/FMOS/FAPH

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No