Anti-malaria MAb in Mali

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Plasmodium Falciparum Infection, Malaria

Intervention / Treatment
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* Biological: VRC-MALMAB0100-00-AB (CIS43LS)
* Other: Normal saline


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose-escalation study: Arm 1: 5 mg/kg of CIS43LS<br>Participants will receive 5 mg/kg of CIS43LS on Day 0. Once all participants in Arm 1 reach Day 7 post-infusion, if no safety concerns have arisen, dosing will begin for Arm 2. | Biological: VRC-MALMAB0100-00-AB (CIS43LS)<br>* Administered via one-time IV infusion<br>|
| Experimental: Dose-escalation study: Arm 2: 10 mg/kg of CIS43LS<br>Participants will receive 10 mg/kg of CIS43LS on Day 0. Once all participants in Arm 2 reach Day 7 post-infusion, if no safety concerns have arisen, dosing will begin for Arm 3. | Biological: VRC-MALMAB0100-00-AB (CIS43LS)<br>* Administered via one-time IV infusion<br>|
| Experimental: Dose-escalation study: Arm 3: 40 mg/kg of CIS43LS<br>Participants will receive 40 mg/kg of CIS43LS on Day 0. After the last participant in Arm 3 reaches Day 7 safety follow-up, an interim safety evaluation will be performed before enrollment begins for the Efficacy study. | Biological: VRC-MALMAB0100-00-AB (CIS43LS)<br>* Administered via one-time IV infusion<br>|
| Experimental: Efficacy study: Arm 1: 10 mg/kg of CIS43LS<br>Participants will receive 10 mg/kg of CIS43LS on Day 0 | Biological: VRC-MALMAB0100-00-AB (CIS43LS)<br>* Administered via one-time IV infusion<br>|
| Experimental: Efficacy study: Arm 2: 40 mg/kg of CIS43LS<br>Participants will receive 40 mg/kg of CIS43LS on Day 0. | Biological: VRC-MALMAB0100-00-AB (CIS43LS)<br>* Administered via one-time IV infusion<br>|
| Placebo Comparator: Efficacy study: Arm 3: Placebo<br>Participants will receive placebo on Day 0. | Other: Normal saline<br>* Administered via one-time IV infusion<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of local AEs occurring within 7 days after the administration of CIS43LS. | Dose escalation study only. | Measured through Day 7 | 
| Severity of local AEs occurring within 7 days after the administration of CIS43LS. | Dose escalation study only. | Measured through Day 7 | 
| Incidence of systemic AEs occurring within 7 days after the administration of CIS43LS. | Dose escalation study only. | Measured through Day 7 | 
| Severity of systemic AEs occurring within 7 days after the administration of CIS43LS. | Dose escalation study only. | Measured through Day 7 | 
| Occurrence of Plasmodium falciparum (Pf) blood stage infection | Detected by microscopic examination of thick blood smear for 24 weeks after administration of CIS43LS or placebo. Efficacy study only. | Measured through Week 24 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose escalation study: measurement of CIS43LS in sera of recipients |  | Measured through Week 24 | 
| Occurrence of Pf blood stage infection | Detected by PCR for 24 weeks after administration of CIS43LS or placebo. Efficacy study only. | Measured through Week 24 | 
| Efficacy study: measurement of CIS43LS in sera of recipients |  | Measured through Week 24 |