Safety and Efficacy of CIS43LS Anti-malaria mAb in Mali

Malaria Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04329104
• Other study ID #: 2020/32/CE/FMOS/FAPH
• Status: Completed
• Phase: Phase 2
• Start date: February 15, 2021
• Est. completion date: July 5, 2023

Study information

• Verified date: April 2024
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 348
• Est. completion date: July 5, 2023
• Est. primary completion date: January 26, 2022
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 18 Years to 55 Years

Eligibility

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 (ß-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.

Related Conditions & MeSH terms

• Malaria
• Plasmodium Falciparum Infection

Intervention

Biological:
• VRC-MALMAB0100-00-AB (CIS43LS)
Administered via one-time IV infusion

Other:
• Normal saline
Administered via one-time IV infusion

Locations

Country	Name	City	State
Mali	Kalifabougou MRTC Clinic	Kalifabougou	Région De Koulikoro
Mali	Torodo MRTC Clinic	Torodo	Région De Koulikoro

Sponsors (4)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Harvard School of Public Health (HSPH), Malaria Research and Training Center, Bamako, Mali, University of Washington

Country where clinical trial is conducted

Mali, 

References & Publications (1)

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, — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	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
Primary	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
Secondary	Participants With Plasmodium Falciparum (Pf) Infection Detected by Microscopic Examination	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.	Day 7 through week 24 (168 days) after administration of intervention
Secondary	Participants With Plasmodium Falciparum (Pf) Infection Detected by RT-PCR	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.	Day 7 through week 24 (168 days)
Secondary	Dose Escalation Study: Measurement of CIS43LS in Sera of Recipients Measurement of CIS43LS in Sera of Recipients - Dose Escalation Study	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.	Measured through Week 24
Secondary	Efficacy Study: Measurement of CIS43LS in Sera of Recipients	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	Measured through Week 24