Anti-malaria MAb in Kenyan Children

Study Overview
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Brief Summary
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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.

Detailed Description
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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 is an age de-escalation and dose-escalation study. 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. 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 10-19 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 10-19 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.

Official Title
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Safety and Efficacy of L9LS, a Human Monoclonal Antibody Against Plasmodium Falciparum, in an Age De-Escalation, Dose-Escalation Trial and a Randomized, Placebo-Controlled, Double-Blind Trial of Children in Western Kenya

Conditions
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Plasmodium Falciparum Infection, Malaria

Intervention / Treatment
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* Drug: L9LS
* Other: Normal Saline


Participation Criteria
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Eligibility Criteria
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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). 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: Taking long-term cotrimoxazole. Participation or planned participation in an interventional trial with an investigational product until 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, authoimmune, renal, oncologic, or hematological) or evidence of any other 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.) 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. 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 within the past 4 weeks 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 enrolment (DP administration) for concomitant prohibited medication. Patients taking any of the following drugs: a. Antimicrobial agents of the following classes (systemic use only): i. Macrolides (e.g. erythromycin, clarithromycin, azithromycin, roxithromycin) ii. Fluoroquinolones (e.g., levofloxacin, moxifloxacin, sparfloxacin) iii. Pentamidine b. Antiarrhythmic agents (e.g. amiodarone, sotalol) c. Antihistamines (e.g. promethazine) d. Antifungals (systemic): ketoconazole, fluconazole, itraconazole e. Antiretrovirals: Saquinavir f. Diuretics (e.g. hydrochlorothiazide, furosemide) g. Antipsychotics (neuroleptics): haloperidol, thioridazine h. Antidepressants: imipramin, citalopram, escitalopram i. 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.

Ages Eligible for Study
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Minimum Age: 5 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Children age 5-10: 5 mg/kg of L9LS<br>Enrolled individuals will receive 5 mg/kg of L9LS via SC injection. | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Placebo Comparator: Part 1: Children age 5-10: Placebo<br>1/4 of children age 5-10 will receive placebo of Normal Saline for comparison. | Other: Normal Saline<br>* Administered subcutaneously.<br>|
| Experimental: Part 1: Children age 5-59 months: 5 mg/kg of L9LS<br> | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 1: Children age 5-10 years: 10 mg/kg of L9LS<br> | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 1: Children age 5-10 years: 20 mg/kg of L9LS<br> | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 1: Children age 5-59 months: 10 mg/kg of L9LS<br> | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 1: Children age 5-59 months: 20 mg/kg of L9LS<br> | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Placebo Comparator: Part 1: Children age 5-59 months: Placebo<br>1/4 of subjects age 5-59 months will receive placebo of Normal Saline for comparison. | Other: Normal Saline<br>* Administered subcutaneously.<br>|
| Experimental: Part 2: Children age 5-17 months: 1 dose L9LS at 10-19 mg/kg<br>Subjects age 5-17 months will receive 1 dose of L9LS via SC injection. | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 2: Children age 5-17 months: 2 doses L9LS at 10-19 mg/kg<br>Subjects age 5-17 months will receive 1 dose of L9LS and a second dose at 6 months via SC injection. | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Placebo Comparator: Part 2: Children age 5-17 months: Placebo<br>1/3 of subjects age 5-17 months will receive placebo of normal saline for comparison. | Other: Normal Saline<br>* Administered subcutaneously.<br>|
| Experimental: Part 2: Children age 18-59 months: 1 dose L9LS at 10-19 mg/kg<br>Subjects age 18-59 months will receive 1 dose L9LS via SC injection. | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Experimental: Part 2: Children age 18-59 months: 2 doses L9LS at 10-19 mg/kg<br>Subjects age 18-59 months will receive 1 dose L9LS, followed by a second dose at 6 months via SC injection. | Drug: L9LS<br>* Administered subcutaneously.<br>|
| Placebo Comparator: Part 2: Children age 18-59 months: Placebo<br>1/3 of subjects age 18-59 months will receive placebo of normal saline for comparison. | Other: Normal Saline<br>* Administered subcutaneously.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS. | Age de-escalation and dose-escalation study | Measured through Day 7 | 
| Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS. | Efficacy study | Measured through Day 7 | 
| Rate of Pf blood-stage infection in participants as detected by microscopic examination of thick blood smear for 52 weeks after administration of two doses of L9LS or placebo. | Efficacy study | Measured through week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Pf blood-stage infection in participants as detected by microscopic examination of thick blood smear after administration of one dose of L9LS or placebo. | Efficacy study | Measured through 12 and 24 weeks after drug or placebo administration | 
| Pf blood-stage infection as detected by microscopic examination of thick blood smear diagnosed by blood smear microscopy after administration of one dose of L9LS or placebo. | Efficacy study | Measured for 52 weeks after drug or placebo administration | 
| Rate of Pf blood-stage infection in participants as detected by RT-PCR of L9LS or placebo. | Efficacy study | Measured at 24 and 52 weeks after drug or placebo administration | 
| Incidence of clinical malaria: an illness accompanied by measured fever ≥37.5°C in the previous 24 hours and Pf asexual parasitemia >5,000 parasites/μL as detected from microscopic examination of thick blood smear. | Age de-escalation, dose-escalation and efficacy study | Measured at 24 and 52 weeks after drug or placebo administration | 
| Incidence of clinical malaria: fever ≥37.5°C, history of fever in the previous 24 hours accompanied by any level of Pf asexual parasitemia, detected from microscopic examination of thick blood smear, requires administration of anti-malarial treatment. | Age de-escalation, dose-escalation and efficacy study | Measured at 24 and 52 weeks after drug or placebo administration | 
| L9LS sera concentration | Age de-escalation, dose-escalation and efficacy study | Through Day 336 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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monoclonal, antibody, Kenya, malaria, children