L9LS MAb in Malian Adults
Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium Falciparum, in a Randomized, Double-Blind, Placebo-Controlled Trial of Adults in Mali
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
A phase 2 trial evaluating the safety and tolerability of a one time subcutaneous (SC) administration of L9LS, as well its protective efficacy against naturally occurring Pf infection over a 6-month malaria season. The primary study hypotheses is that L9LS will be safe and protective against malaria infection. As a secondary objective, the efficacy of L9LS within three body weight strata among female participants will each be compared to placebo. Before study agent administration, all subjects will be given artemether lumefantrine to clear any preexisting Pf blood stage infection.
The study is a randomized, double-blind, placebo-controlled, sex-stratified (2:1 female to male ratio) and weight-stratified trial (N=288 total) with 2 treatment arms: L9LS 900 mg SC (n=216) and placebo (n=72) to assess safety and protective efficacy of L9LS compared to placebo.
Subjects 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 examination and blood collection for identification of Pf infection and other research laboratory evaluations.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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Région De Koulikoro
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Faladiè, Région De Koulikoro, Mali
- Faladje MRTC Clinic
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Kalifabougou, Région De Koulikoro, Mali
- Kalifabougou MRTC Clinic
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Torodo, Région De Koulikoro, Mali
- Torodo MRTC Clinic
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
- Females aged ≥18 and ≤49 years and weighing ≥ 45.0 and ≤ 90.0 kg.
- Males aged ≥18 and ≤55 years and weighing ≥ 50.0 and ≤ 100.0 kg.
- 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, Faladje, 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 tests 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; 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; participation in the placebo arm of the Mali adult CIS43LS MAb trial (ClinicalTrials.gov Identifier: NCT04329104) 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.
- Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors).
- 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 or monoclonal antibody 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: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
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Experimental: L9LS 900 mg
Adult participants receive a single dose of L9LS 900 mg subcutaneously.
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Administered one time via subcutaneous route.
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Placebo Comparator: Placebo
Adult participants receive a single dose of Placebo subcutaneously.
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Normal saline administered one time via subcutaneous route.
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Number of Participants With Local Adverse Events (AEs)
Time Frame: Within 7 days after administration of intervention
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Number of participants with local adverse events occurring within 7 days after administration of L9LS.
Local reactogenicity included pain/tenderness, swelling, redness, bruising, and pruritus at the site of infusion.
Adverse events were captured by Investigator examination and history from participants.
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Within 7 days after administration of intervention
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Number of Participants With Systemic Adverse Events (AEs)
Time Frame: Within 7 days after administration of intervention
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Number of participants with local adverse events occurring within 7 days after administration of L9LS.
Systemic reactogenicity events included fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint pain.
Adverse events were captured by Investigator examination and history from participants.
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Within 7 days after administration of intervention
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Number of Participants With Local Adverse Events (AEs) (by Grade)
Time Frame: Within 7 days after administration of intervention
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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 administration of intervention
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Number of Participants With Systemic Adverse Events (AEs) (by Grade)
Time Frame: Within 7 days after administration of intervention
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The severity of systemic adverse events occurring after the administration of L9LS 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 administration of intervention
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Participants With Plasmodium Falciparum (Pf) Infection Detected by Microscopic Examination for Thick Blood Smear
Time Frame: Day 7 through week 24
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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 L9LS or placebo.
Sample was collected every two weeks from day seven until week 24.
Analysis was done as number of participants who had at least one positive blood smear.
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Day 7 through week 24
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
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Participants With Plasmodium Falciparum (Pf) Infection Detected by Real-Time Polymerase Chain Reaction (RT-PCR)
Time Frame: Day 7 through week 24
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Number of participants with Plasmodium falciparum (Pf) blood stage infection defined as blood sample positive for Pf was assessed by real-time polymerase chain reaction (RT-PCR) of blood sample collected from participants from day 7 through week 24 (168 days) after administration of L9LS or placebo.
Sample was collected every two weeks from day seven until week 24.
Analysis was done as number of participants who had at least one positive blood sample.
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Day 7 through week 24
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Maximum Total Plasma Concentration (Cmax) for L9LS
Time Frame: Measure through week 24
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Maximum total plasma concentration (Cmax) following a 900 mg dose of L9LS.
Serum collected on days 0, 1, 7, 14, 28, 56, 84, 112, 140, & 168 after the administration of L9LS.
Cmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles postdose.
Analysis was done to determine each participant's observed maximum concentration based on all available timepoints and cumulative output was calculated as the central tendency and dispersion metric based on the observed maximum concentrations.
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Measure through week 24
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Time to Maximum Plasma Concentration (TMax) for L9LS - Hours
Time Frame: Day 7 post administration of drug
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Time to maximum total plasma concentration (Cmax) following a 900 mg dose of L9LS on day 7 post administration of drug.
Tmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles.
Analysis was done to determine the time (in hours) at which the maximum observed concentration was achieved for each participant and cumulative output was calculated as the central tendency and dispersion metric based on the observed time of maximum concentration.
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Day 7 post administration of drug
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Time to Maximum Plasma Concentration (TMax) for L9LS - Days
Time Frame: Measure through week 24
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Time to maximum total plasma concentration (Cmax) following a 900 mg dose of L9LS.
Serum collected on days 0, 1, 7, 14, 28, 56, 84, 112, 140, & 168 after the administration of L9LS.
Tmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles.
Analysis was done to determine the time (in days) at which the maximum observed concentration was achieved for each participant and cumulative output was calculated as the central tendency and dispersion metric based on the observed time of maximum concentration.
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Measure through week 24
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Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Kassoum Kayentao, MD, MPH, PhD, Faculté de Médecine Pharmacie d'Odontostomatologie (FMPOS)
- Principal Investigator: Peter Crompton, MD, MPH, National Institutes of Health (NIH)
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Actual)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- 2023/109/CE/USTTB
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
IPD Plan Description
Human data generated in this study for future research will be shared as follows:
- De-identified or identified data with approved outside collaborators under appropriate agreements.
- De-identified results or data in publication and/or public presentations.
IPD Sharing Time Frame
IPD Sharing Access Criteria
IPD Sharing Supporting Information Type
- STUDY_PROTOCOL
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
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