Anti-malaria MAb in Kenyan Children

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Completed; Phase 2

Conditions: Malaria; Plasmodium Falciparum Infection

Treatments: Other: Placebo; Drug: L9LS

Study type: Interventional

Funder types: Other; Other U.S. Federal agency; NIH

Identifiers

NCT05400655

SERU 4413

Details and patient eligibility

About

The purpose of this study is to evaluate the safety and tolerability of one-time subcutaneous (SC) administration of monoclonal antibody (MAb) L9LS in healthy Kenyan children aged 5 months to 10 years, as well as the protective efficacy of one or two doses of L9LS against naturally occurring Plasmodium falciparum (Pf) infection among Kenyan children aged 5 to 59 months at enrollment, in a setting of perennial high transmission.

Full description

A two-part, phase 2 trial evaluating the safety and tolerability of one-time subcutaneous (SC) administration of monoclonal antibody (MAb) L9LS in healthy Kenyan children aged 5 months to 10 years, as well as the protective efficacy of one or two doses of L9LS against naturally occurring Plasmodium falciparum (Pf) infection among Kenyan children aged 5 to 59 months at enrollment, in a setting of perennial high transmission.

Part 1 includes part 1a and part 1b and is an age de-escalation and dose-escalation study. In part 1a, in a stepwise fashion, children aged 5-10 years will receive 5 mg/kg of L9LS or placebo and be followed for 3 months to assess tolerability and safety. If acceptable tolerability and safety profiles are met at 1-week post-injection, the 5 mg/kg dose of L9LS or placebo will be administered to children aged 5-59 months while enrolling another cohort of children aged 5-10 years at a dose of 10 mg/kg of L9LS or placebo. If after 1 week, the 10 mg/kg dose is found to be safe in children aged 5-10 years and the 5 mg/kg dose is found to be safe in children aged 5-59 months, a 20 mg/kg dose of L9LS or placebo will be administered to children aged 5-10 years and a 10 mg/kg dose of L9LS or placebo to children aged 5-59 months. Finally, if these doses are found safe after 1 week, a 20 mg/kg dose of L9LS or placebo will be administered to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, part 2 of the trial will begin. Part 1b of the study was added later and will include two additional dose escalation cohorts of children aged 5 to 71 months and will test 30 mg/kg L9LS and 40 mg/kg L9LS. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. 12 participants in each age-dose group will be enrolled in a 3:1 ratio of L9LS to placebo, and all participants will be followed for a total of 3 months.

Part 2 is the efficacy study. Children 5-59 months of age will be randomized to receive a 10-20 mg/kg dose of L9LS or placebo by SC administration. There will be two L9LS cohorts, one 5-17 months of age and another 18-59 months of age, which will constitute one L9LS arm. A placebo arm will be composed of children 5-59 months of age. They will be followed over 12 months with monthly blood smear microscopy and polymerase chain reaction (PCR) and twice-monthly symptomatology and careseeking behavior questionnaires. Dosing will be based on three weight bands; all doses will be administered SC with fixed doses of 75 mg L9LS, 150 mg L9LS, or 225 Mg L9LS, resulting in a range of 10-20 mg/kg in a double-blinded fashion. Blood will be drawn to assess antibody titers at baseline, and at three additional time points over 12 months to establish pharmacokinetics (PK). Participants in the L9LS arm will be randomized 1:1 at baseline to receive either a second L9LS injection or a placebo injection to evaluate the additional efficacy of a second dose administered 6 months after the first dose. (Those in the placebo arm will receive a second injection of placebo.) Participants will be followed for an additional 6 months after the second injection with monthly blood smear microscopy and PCR, and a blood draw at month 11 to assess L9LS PK.

Enrollment: 912 patients

Sex: All

Ages: 5 months to 10 years old

Volunteers: Accepts Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

Healthy children aged 5 months to 10 years (Part 1) or 5-59 months (Part 2). Weight ≥5 kg and weight ≤30 kg (Part 1) or weight ≥5 kg and ≤22.5 kg (Part 2) or weight ≥5 kg and ≤20 kg (for 30 mg/kg group) or weight ≥5 kg and ≤15 kg (for 40 mg/kg group), to ensure a maximum volume of two 2-mL (Part 1b) Hemoglobin level ≥8 g/dL. Height and weight Z-scores >-2. Living within Alego-Usonga sub-county. Able to participate for the duration of the trial. Parent and/or guardian of participant able to provide informed consent.

Exclusion Criteria

Individuals meeting any of the following criteria will be excluded from study participation:

Taking long-term cotrimoxazole. Participation or planned participation in any other interventional trial with an investigational product prior to the last required protocol visit or receipt of an investigational product within the past 30 days. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.) Received any doses of any malaria vaccine. Participation in part 1 of this study (for individuals being screened for enrollment into part 2) Age < 12 months at the time the RTS,S/AS01 vaccine is anticipated to become available in the whole of Siaya County Current significant medical condition (neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, renal, oncologic, or hematological) or evidence of any serious underlying medical condition identified by medical history, physical examination, or laboratory examination.

Known sickle cell disease. (Note: Known sickle cell trait is NOT exclusionary.) 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 values that are not clinically significant (ie., do not require any repeat or follow-up).

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 values that are not clinically significant.) Infected with HIV. History of a severe allergic reaction or anaphylaxis. Severe asthma (defined as asthma that is unstable or required emergency 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, Sjogren's syndrome, or autoimmune thrombocytopenia.

Known immunodeficiency syndrome. 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.

Known asplenia or functional asplenia. Clinical signs of malnutrition. Receipt of immunoglobulins and/or blood products within the past 6 months. 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/guardian study comprehension examination score of <80% correct or per investigator discretion.

Receipt of a live vaccine or a killed vaccine within the past 2 weeks prior to study agent administration.

Known allergies or contraindication to dihydroartemisinin-piperaquine.

Use or known need at the time of pre-enrolment (DP administration) of concomitant prohibited medication, including:

Antimicrobial agents of the following classes (systemic use only):

Macrolides (e.g. erythromycin, clarithromycin, azithromycin, roxithromycin) Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin) Pentamidine Antiarrhythmic agents (e.g. amiodarone, sotalol) Antihistamines (e.g. promethazine) Antifungals (systemic): ketoconazole, fluconazole, itraconazole Antiretrovirals: Saquinavir Diuretics (e.g. hydrochlorothiazide, furosemide) Antipsychotics (neuroleptics): haloperidol, thioridazine Antidepressants: imipramine, citalopram, escitalopram Antiemetics: domperidone, chlorpromazine, ondansetron Increased risk of salivary gland hypofunction (dryness of the mouth, swelling under the tongue and/or below the ear, halitosis) History of any other illness or condition which, in the investigator's judgment, may substantially increase the risk associated with the subject's participation in the protocol or compromise the scientific objectives, or 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.

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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912 participants in 22 patient groups, including a placebo group

Age de-escalation and dose-escalation study: Arm 1a: Age 5-10 years, 5 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-10 years receive a single dose of 5 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 2.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 1b: Age 5-10 years, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-10 years receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 2.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 2a: Age 5-59 months, 5 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-59 months receive a single dose of 5 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 2b: Age 5-59 months, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 2c: Age 5-10 years, 10 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-10 years receive a single dose of 10 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 2d: Age 5-10 years, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-10 years receive a single dose placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 3.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 3a: Age 5-10 years, 20 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-10 years receive a single dose of 20 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 3b: Age 5-10 years, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-10 years receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 3c: Age 5-59 months, 10 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-59 months receive a single dose of 10 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 3d: Age 5-59 months, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 4.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 4a: Age 5-59 months, 20 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-59 months receive a single dose of 20 mg/kg of L9LS one-time via subcutaneous administration.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 4b: Age 5-59 months, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-59 months receive a single dose of placebo via subcutaneous administration.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 5a: Age 5-71 months, 30 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-71 months receive a single dose of 30 mg/kg L9LS via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 6.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 5b: Age 5-71 months, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-71 months receive a single dose of placebo via subcutaneous administration. Once subjects reach day 7 post-administration without safety concerns dosing begins for arm 6.

Treatment:

Other: Placebo

Age de-escalation and dose-escalation study: Arm 6a: Age 5-71 months, 40 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-71 months receive a single dose of 40 mg/kg L9LS via subcutaneous administration.

Treatment:

Drug: L9LS

Age de-escalation and dose-escalation study: Arm 6b: Age 5-71 months, Placebo

Placebo Comparator group

Description:

Healthy children aged 5-71 months receive a single dose of placebo via subcutaneous administration.

Treatment:

Other: Placebo

Efficacy Study: Arm 1a: Age 5-17 months, 10-20 mg/kg of L9LS/Placebo

Experimental group

Description:

Healthy children aged 5-17 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.

Treatment:

Drug: L9LS

Other: Placebo

Efficacy Study: Arm 1b: Age 5-17 months, 10-20 mg/kg of L9LS/10-20 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 5-17 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a second single dose of 10-20 mg/kg L9LS via subcutaneous administration.

Treatment:

Drug: L9LS

Efficacy Study: Arm 1c: Age 5-17 months, Placebo/Placebo

Placebo Comparator group

Description:

Healthy children aged 5-17 months receive a single dose of placebo via subcutaneous administration. Six months later, participants receive a second single dose of placebo via subcutaneous administration.

Treatment:

Other: Placebo

Efficacy Study: Arm 2a: Age 18-59 months, 10-20 mg/kg of L9LS/Placebo

Experimental group

Description:

Healthy children aged 18-59 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a single dose of placebo via subcutaneous administration.

Treatment:

Drug: L9LS

Other: Placebo

Efficacy Study: Arm 2b: Age 18-59 months, 10-20 mg/kg of L9LS/10-20 mg/kg of L9LS

Experimental group

Description:

Healthy children aged 18-59 months receive a single dose of 10-20 mg/kg L9LS via subcutaneous administration. Six months later, participants receive a second single dose of 10-20 mg/kg L9LS via subcutaneous administration.

Treatment:

Drug: L9LS

Efficacy Study: Arm 2c: Age 18-59 months, Placebo/Placebo

Placebo Comparator group

Description:

Healthy children aged 18-59 months receive a single dose of placebo via subcutaneous administration. Six months later, participants receive a second single dose of placebo via subcutaneous administration.

Treatment:

Other: Placebo