Safety and Efficacy of CIS43LS Anti-malaria mAb in Mali

Phase 2

Completed

Conditions: Malaria
Plasmodium Falciparum Infection

Interventions: Other: Normal saline
Biological: VRC-MALMAB0100-00-AB (CIS43LS)

Registration Number: NCT04329104

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 348

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 Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

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

Primary Outcome Measures

Name	Time	Method
Severity of Systemic Adverse Events (AEs)	Within 7 days after the administration of CIS43LS	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
Participants With Local Adverse Events (AEs)	Within 7 days after administration of CIS43LS	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.
Participants With Systemic Adverse Events (AEs)	Within 7 days after the administration of CIS43LS	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.
Severity of Local Adverse Events (AEs)	Within 7 days after the administration of CIS43LS	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

Secondary Outcome Measures

Name	Time	Method
Efficacy Study: Measurement of CIS43LS in Sera of Recipients	Measured through Week 24	Efficacy Study only Concentrations of CIS43LS will be measured by a Meso Scale Discovery LLC-based automation platform. The concentration at the visit prior to the first Pf infection will be used to assess CIS43LS-mediated protection. Concentrations of CIS43LS in blood will
Participants With Plasmodium Falciparum (Pf) Infection Detected by Microscopic Examination	Day 7 through week 24 (168 days) after administration of intervention	The incidence of 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.
Dose Escalation Study: Measurement of CIS43LS in Sera of Recipients Measurement of CIS43LS in Sera of Recipients - Dose Escalation Study	Measured through Week 24	Concentrations of CIS43LS will be measured by a Meso Scale Discovery LLC-based automation platform. The concentration at the visit prior to the first Plasmodium Falciparum (Pf) infection will be used to assess CIS43LS-mediated protection. Concentrations of CIS43LS in blood will help assess durability of CIS43LS at each dose level and will allow for correlation with Pf infection risk.
Participants With Plasmodium Falciparum (Pf) Infection Detected by RT-PCR	Day 7 through week 24 (168 days)	The occurrence of 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 7 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.

Trial Locations

Locations (2): Torodo MRTC Clinic
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Torodo, Région De Koulikoro, Mali
Kalifabougou MRTC Clinic
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Kalifabougou, Région De Koulikoro, Mali

Related News

nih.gov

2 years ago

Monoclonal antibody prevents malaria infection in African adults

A monoclonal antibody, CIS43LS, was found up to 88.2% effective in preventing malaria in African adults during a six-month malaria season, offering a new tool for malaria prevention in endemic regions. The NIH-sponsored trial highlights the potential for monoclonal antibodies to complement existing malaria interventions.