Anti-malaria MAb in Malian Children

The purpose of this study is to evaluate the safety and tolerability of onetime subcutaneous (SC) or intravenous (IV) administration of monoclonal antibody (MAb) L9LS in healthy Malian adults and one-time SC administration of L9LS in healthy Malian children, as well as its protective efficacy against naturally occurring Plasmodium falciparum (Pf) infection over a 7-month malaria season in healthy Malian children 6-10 years of age.

A two-part, phase 2 trial evaluating the safety and tolerability of onetime subcutaneous (SC) or intravenous (IV) administration of monoclonal antibody (MAb) L9LS in healthy Malian adults and one-time SC administration of L9LS in healthy Malian children, as well as its protective efficacy against naturally occurring Plasmodium falciparum (Pf) infection over a 7-month malaria season in healthy Malian children 6-10 years of age.

The first part of the study is an age de-escalation and dose-escalation study for safety and tolerability. Adult subjects in the dose-escalation study will be assigned in open-label fashion to 1 of 3 L9LS dose arms. Dosing will begin in the lowest dose arm. Once all subjects in that arm reach day 7 post-administration, if no safety concerns have arisen, dosing will begin at the next dose level. Once all subjects in that arm reach day 7 post-administration, if no safety concerns have arisen, dosing will begin at the highest dose level. Once all adult subjects reach day 7 post-administration, if no safety concerns have arisen, 18 subjects aged 6-10 years will be randomized 1:1 to L9LS or placebo in double-blind fashion. Once all 18 subjects reach day 7 post-administration, if no safety concerns have arisen, an additional 18 subjects aged 6-10 years will be randomized 1:1 to L9LS versus placebo. Randomization of subjects aged 6-10 years in each L9LS dose arm will be weight-stratified and enrollment will be weight de-escalated. Adult subjects will be followed for safety to assess adverse events (AEs) at study visits 1, 3, 7, 14, 21, and 28 days after administration, and once every month thereafter through 28 weeks. Subjects aged 6-10 years will be followed at study visits 1, 3, 7, 14, 21, and 28 days after administration, and once every 2 weeks thereafter through 28 weeks. Primary study assessments include physical examination and blood collection for identification of Pf infection and other research laboratory evaluations. After the last subject in the pediatric L9LS dose arm reaches day 7 safety follow-up, an interim safety evaluation will be performed before enrollment begins for the efficacy part of the study. Data from the 36 subjects aged 6-10 years enrolled in the dose-escalation study will be included in a secondary analysis to determine the relationship between L9LS concentration and the risk of Pf infection.

The second part of the study is a weight-stratified, randomized, double-blind, placebo-controlled trial to assess safety and protective efficacy of L9LS versus placebo administered SC in children 6-10 years of age. In this part of the study, subjects will be randomized to L9LS or placebo. Randomization of subjects in each arm will be weight-stratified. Subjects in the efficacy study will receive the study agent prior to the malaria season and be followed at study visits 1, 3, 7, 14, 21, and 28 days later, and once every 2 weeks thereafter through 28 weeks. Primary study assessments include physical examination and blood collection for identification of Pf infection and other research laboratory evaluations.

Prior to the last study visit of the original protocol described above (January 2023 - February 2023), study participants who remain enrolled in the dose-escalation and efficacy studies will be invited to participate in a 12-month extension study. After the safety and efficacy results are unblinded (approximately March/April 2023), participants who agree to continue with the extension will be grouped into one of 3 arms based on their original study arm assignment:

Arm 1: Up to 84 subjects who received 150 mg of L9LS in year 1 (9 from the dose-escalation study, plus 75 from the efficacy study).

Arm 2: Up to 84 subjects who received 300 mg of L9LS in year 1 (9 from the dose-escalation study, plus 75 from the efficacy study).

Arm 3: Up to 93 subjects who received placebo in year 1 (18 from the dose-escalation study, plus 75 from the efficacy study).

The protocol extension employs a pre-specified, adaptive design based on the time-to-event efficacy of 150 mg and 300 mg of L9LS against P. falciparum infection as detected by blood smear observed after the first malaria season in the original protocol. Specifically, if 150 mg and 300 mg of L9LS both show ≥60% efficacy during the first malaria season (based on the upper bound of the two-sided 95% confidence interval \[CI\]), participants will be re-randomized 1:1 in a double-blind fashion within each arm to receive a single dose of either L9LS (150 or 300 mg depending on study arm) or placebo administered SC before the 2023 malaria season.

The same randomization scheme will be followed if in the first malaria season the 300-mg dose of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 95% CI) and the 150-mg dose of L9LS shows \<60% efficacy (based on the upper bound of the two-sided 95% CI) but the difference between their respective point estimates of efficacy is ≤10%, with the exception that children who received placebo in year 1 will receive 300 mg of L9LS (or placebo) in year 2.

If 300 mg of L9LS shows ≥60% efficacy (based on the upper bound of the two-sided 95% CI) and 150 mg of L9LS shows \<60% efficacy (based on the upper bound of the two-sided 95% CI) but the difference between their respective point estimates of efficacy is \>10% during the first malaria season, participants will be re-randomized 1:1 in a double-blind fashion within each arm to receive a single dose of either 300 mg of L9LS or placebo administered SC before the 2023 malaria season.

If 150 mg and 300 mg of L9LS both show \<60% efficacy (based on the upper bound of the two-sided 95% CI) after the first malaria season, the protocol extension will be abandoned.

Before study agent administration, all subjects will be given artemether-lumefantrine to clear any preexisting Pf blood-stage infection.

Subjects will be followed at study visits 1, 3, 7, 14, 21, and 28 days after administration, and once every 2 weeks thereafter through 28 weeks, with a final visit occurring on study day 252 (36 weeks) to collect a final PK sample. Primary study assessments include medical history, physical examination, and blood collection for pharmacokinetics (PK), anti-drug antibody (ADA) assessments, identification of Pf infection by microscopic examination of thick blood smears and RT-PCR, and other research laboratory evaluations.

Eligibility Criteria:
Inclusion Criteria:

* Is within the appropriate age range for the respective cohort:

  1. Children: Aged ≥6 years and \<11 years.
  2. Adults: Aged ≥18 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.
* Adult participants or parent and/or guardian of minor participants 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.
* For the adult cohort, 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.

Year 2 Extension Inclusion Criteria:

* Participated in the first year of the protocol.
* 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.
* Parent and/or guardian 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.

Exclusion Criteria:

* Body weight \<15 kg or \>30 kg for children, or \>60 kg for adults.
* Currently receiving or planning to receive seasonal malaria chemoprevention (SMC).
* Any history of menses (for 6-10 year old cohort) or positive pregnancy test at screening (for adult cohort).
* 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.
* Subject (for adult subjects) or parental (for minor subjects) 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 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 before 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).
* Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors).
* Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren'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 or COVID-19 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.
* Clinical signs of malnutrition.
* 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.

Year 2 Extension Exclusion Criteria:

* Currently receiving or planning to receive SMC.
* Any history of menses.
* 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.
* Parental 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 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 another interventional trial with an investigational product other than L9LS 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).
* Currently active salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors).
* Pre-existing autoimmune or antibody-mediated diseases including but not limited to: systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren'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 or COVID-19 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 any other monoclonal antibody other than L9LS in the last 5 years.
* Known allergies or contraindication against artemether-lumefantrine.
* Clinical signs of malnutrition.
* 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.