| Protocol No: | ECCT/22/05/03 | Date of Protocol: | 28-03-2022 |
| Study Title: | 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 |
| Study Objectives: | Primary Objectives: Part 1:
Part 2:
1. To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo. 2. To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo. 3. To evaluate the efficacy of L9LS at 10-19 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo. 4. To assess protection of L9LS at 10-19 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo. 5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age. 6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-19 mg/kg (part 2) in healthy Kenyan children, and a. To correlate L9LS serum concentration with Pf infection risk. To correlate L9LS serum concentration with clinical malaria risk. |
| 1 | Primary 1. Part 1: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children. 2. Part 2: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-20 mg/kg by SC administration to healthy Kenyan children 3. Part 2: Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-20 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo. Secondary 1. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo. 2. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo. 3. To evaluate the efficacy of L9LS at 10-20 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo. 4. To assess protection of L9LS at 10-20 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo. 5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age. 6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age. 7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-20 mg/kg (part 2) in healthy Kenyan children, and a. To correlate L9LS serum concentration with Pf infection risk. b. To correlate L9LS serum concentration with clinical malaria risk. Tertiary/Exploratory 1. To assess the impact of L9LS on hospitalizations with malaria 2. To determine whether ADA to L9LS can be detected in sera of recipients at specific timepoints throughout the study. 3. To assess for IgG1 allotypes and allotype specific effects on L9LS PK. 4. To determine if the efficacy of L9LS is specific to certain Pf parasite genotypes at the CSP locus. 5. To explore the impact of pre existing parasitemia on the protective efficacy and PK of L9LS. 6. To explore the impact of pre existing CSP antibodies on the protective efficacy and PK of L9LS. 7. To assess the effect of L9LS on antibodies to measles in the younger age group. 8. To compare the efficacy of one versus two doses of L9LS against Pf infection and clinical malaria over 12 months. |
| 3 | Primary objectives 1. Part 1: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children. 2. Part 2: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-20 mg/kg by SC administration to healthy Kenyan children 3. Part 2: Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-20 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo. Secondary objectives 1. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo. 2. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo. 3. To evaluate the efficacy of L9LS at 10-20 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo. 4. To assess protection of L9LS at 10-20 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo. 5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age. 6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age. 7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-20 mg/kg (part 2) in healthy Kenyan children, and a. To correlate L9LS serum concentration with Pf infection risk. b. To correlate L9LS serum concentration with clinical malaria risk. Tertiary/Exploratory objectives 1. To assess the impact of L9LS on hospitalizations with malaria 2. To determine whether ADA to L9LS can be detected in sera of recipients at specific timepoints throughout the study. 3. To assess for IgG1 allotypes and allotype specific effects on L9LS PK. 4. To determine if the efficacy of L9LS is specific to certain Pf parasite genotypes at the CSP locus. 5. To explore the impact of pre existing parasitemia on the protective efficacy and PK of L9LS. 6. To explore the impact of pre existing CSP antibodies on the protective efficacy and PK of L9LS. 7. To assess the effect of L9LS on antibodies to measles in the younger age group. 8. To compare the efficacy of one versus two doses of L9LS against Pf infection and clinical malaria over 12 months. Follow-on Study Primary Objectives Follow-on Safety (part 1b) 1. To evaluate the safety and tolerability of L9LS administered at doses of 30 mg/kg and 40 mg/kg by SC administration to healthy Kenyan children. Follow-on Part 2 Extension 2. To evaluate the safety and tolerability of a third and fourth SC dose of L9LS at 20–40 mg/kg (compared to placebo) in healthy Kenyan children. 3. To evaluate the PK of L9LS throughout the follow-up phase at 20–40 mg/kg in healthy Kenyan children. 4. To determine if ADAs to L9LS can be detected in sera of recipients at specific timepoints throughout the study and to correlate the occurrence of ADAs with L9LS PK. Extension Phase Exploratory Objectives (see Figure 4 for study arm definitions) 1. To assess the efficacy of an additional one or two SC doses of L9LS over one year at 20–40 mg/kg in mediating protection against Pf infection and clinical malaria in healthy Kenyan children during a second year of follow-up compared to those who received placebo only (arms 1 vs. 3; arms 2 vs. 3) and in those receiving two L9LS doses in the extension versus one (arms 1 vs. 2) 2. To evaluate the PK of L9LS throughout the study and to correlate L9LS serum concentration with Pf infection risk and clinical malaria risk 3. To evaluate the effect of a third (and fourth) dose of L9LS on development of acquired immunity (measured by antibodies) |
| 4 | Primary Objectives 1. Part 1: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children. 2. Part 2: Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-20 mg/kg by SC administration to healthy Kenyan children 3. Part 2: Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-20 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo. Secondary 1. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo. 2. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo. 3. To evaluate the efficacy of L9LS at 10-20 mg/kg against first/only Pf malaria infection as detected by PCR over 3, 6 and 12 months compared to placebo. 4. To assess protection of L9LS at 10-20 mg/kg against clinical malaria (first/only and all episodes) at 3, 6 and 12 months compared to a placebo. 5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age. 6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age. 7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-20 mg/kg (part 2) in healthy Kenyan children, and a. To correlate L9LS serum concentration with Pf infection risk. b. To correlate L9LS serum concentration with clinical malaria risk. Tertiary/Exploratory 1. To assess the impact of L9LS on hospitalizations with malaria 2. To determine whether ADA to L9LS can be detected in sera of recipients at specific timepoints throughout the study. 3. To assess for IgG1 allotypes and allotype specific effects on L9LS PK. 4. To determine if the efficacy of L9LS is specific to certain Pf parasite genotypes at the CSP locus. 5. To explore the impact of pre existing parasitemia on the protective efficacy and PK of L9LS. 6. To explore the impact of pre existing CSP antibodies on the protective efficacy and PK of L9LS. 7. To assess the effect of L9LS on antibodies to measles in the younger age group. 8. To compare the efficacy of one versus two doses of L9LS against Pf infection and clinical malaria over 12 months. Follow-on Study Primary Objectives Follow-on Safety (part 1b) 1. To evaluate the safety and tolerability of L9LS administered at doses of 30 mg/kg and 40 mg/kg by SC administration to healthy Kenyan children. Follow-on Part 2 Extension 2. To evaluate the safety and tolerability of a third and fourth SC dose of L9LS at 20–40 mg/kg (compared to placebo) in healthy Kenyan children. 3. To evaluate the PK of L9LS throughout the follow-up phase at 20–40 mg/kg in healthy Kenyan children. 4. To determine if ADAs to L9LS can be detected in sera of recipients at specific timepoints throughout the study and to correlate the occurrence of ADAs with L9LS PK. Extension Phase Exploratory Objectives 1. To assess the efficacy of an additional one or two SC doses of L9LS over one year at 20–40 mg/kg in mediating protection against Pf infection and clinical malaria in healthy Kenyan children during a second year of follow-up compared to those who received placebo only (arms 1 vs. 3; arms 2 vs. 3) and in those receiving two L9LS doses in the extension versus one (arms 1 vs. 2) 2. To evaluate the PK of L9LS throughout the study and to correlate L9LS serum concentration with Pf infection risk and clinical malaria risk 3. To evaluate the effect of a third (and fourth) dose of L9LS on development of acquired immunity (measured by antibodies) |
| Laymans Summary: |
Malaria is a disease that affects many people in the world, more so in sub-Saharan Africa. It is caused by parasites carried by mosquitoes. When the mosquitoes bite people, the parasites can pass into their blood and cause illness, which if not treated in a timely manner or sufficiently, can cause severe illness or even death. In effect, despite there being medicines to cure malaria, it is still responsible for a huge number of admissions and deaths, especially in Africa. This informs the need to come up with new ways to reduce the impact of malaria, for example, through preventing people from getting malaria in the first place.
This is a research study to test an experimental drug, called L9LS, for malaria. L9LS is a type of drug called a monoclonal antibody. Antibodies are natural products made by the human body to fight infection by blocking germs such as bacteria and parasites. Monoclonal means that all the antibodies in the drug are exactly the same. The study drug stays in the blood for several months and blocks the parasite that causes malaria. We hope that, if enough of the drug is in the blood, it will prevent people from getting malaria.
The study aims to find out how safe the drug is and whether it prevents malaria and if so, to what extent. This study will be conducted in two parts. In the first part, involving 72 participants, the study will investigate how safe and well tolerated three different increasing doses of the study drug are by administering each dose to older children first (5-10 years of age) then to younger children (5-59 months of age) 1 week after each different dose, if it is well tolerated and safe in the older age group. The study will proceed to part 2 if the doses are safe and well tolerated in the younger age group, as determined by a data safety and monitoring board. The second part of the study will investigate whether the drug prevents malaria, and if so, to what extent. It will enroll an equal number of children aged between 5-17 months and those aged 18-59 months, totalling to about 324 participants. Each age category will further have 3 groups of children assigned by chance to each group. The first group will receive two doses of the study drug 6 months apart, the 2nd group will receive the study drug then placebo (saltwater/an inactive substance similar to study drug) 6 months after, and the 3rd group will receive two doses of the placebo 6 months part.
Other objectives which will be explored by the study include comparing the study drug level with the possibility of getting a malaria infection or detecting malaria parasites in the blood.
The study will take place at Siaya County Referral Hospital and Kogelo Dispensary, both in Siaya County, western Kenya. The study duration will be approximately 24 months, with a participant in Part 1 of the study taking 4-5 months and a participant in Part 2 of the study taking 13-14 months.
The study procedures in Part 1 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial followed by the study drug or placebo after 2 weeks. They will then have another 10 study visits within a 3 months period to monitor various safety measures. The study procedures in Part 2 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial followed by the study drug or placebo after 2 weeks. They will then have a study visit every month up to end of month 6 when they will receive the 2nd dose of either the study drug or placebo. Other follow up visits will be conducted monthly until end of 12 months from the date of initial study drug or placebo dose. These follow-up visits will assess both safety and efficacy measures.
The study will provide information on the safety and usefulness of L9LS as a therapy used in
the prevention of malaria.
|
| 3 | Malaria is a disease that affects many people in the world, more so in sub-Saharan Africa. It is caused by parasites carried by mosquitoes. When the mosquitoes bite people, the parasites can pass into their blood and cause illness, which if not treated in a timely manner or sufficiently, can cause severe illness or even death. In effect, despite there being medicines to cure malaria, it is still responsible for a huge number of admissions and deaths, especially in Africa. This informs the need to come up with new ways to reduce the impact of malaria, for example, through preventing people from getting malaria in the first place. This is a research study to test an experimental drug, called L9LS, for malaria. L9LS is a type of drug called a monoclonal antibody. Antibodies are natural products made by the human body to fight infection by blocking germs such as bacteria and parasites. Monoclonal means that all the antibodies in the drug are exactly the same. The study drug stays in the blood for several months and blocks the parasite that causes malaria. We hope that, if enough of the drug is in the blood, it will prevent people from getting malaria. The study aims to find out how safe the drug is and whether it prevents malaria and if so, to what extent. This study will be conducted in two parts. In the first part, involving 72 participants, the study will investigate how safe and well tolerated three different increasing doses of the study drug are by administering each dose to older children first (5-10 years of age) then to younger children (5-59 months of age) 1 week after each different dose, if it is well tolerated and safe in the older age group. The study will proceed to part 2 if the doses are safe and well tolerated in the younger age group, as determined by a data safety and monitoring board. The second part of the study will investigate whether the drug prevents malaria, and if so, to what extent. It will enroll an equal number of children aged between 5-17 months and those aged 18-59 months, totaling to about 324 participants. Each age category will further have 3 groups of children assigned by chance to each group. The first group will receive two doses of the study drug 6 months apart, the 2nd group will receive the study drug then placebo (saltwater/an inactive substance similar to study drug) 6 months after, and the 3rd group will receive two doses of the placebo 6 months part. Other objectives which will be explored by the study include comparing the study drug level with the possibility of getting a malaria infection or detecting malaria parasites in the blood. The study will take place at Siaya County Referral Hospital and Kogelo Dispensary, both in Siaya County, western Kenya. The study duration will be approximately 24 months, with a participant in Part 1 of the study taking 4-5 months and a participant in Part 2 of the study taking 13-14 months. The study procedures in Part 1 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial followed by the study drug or placebo after 2 weeks. They will then have another 10 study visits within a 3 months period to monitor various safety measures. The study procedures in Part 2 will entail assessing participant eligibility, getting consent and enrollment into the study. On enrollment, participants will receive a standard dose of antimalarial followed by the study drug or placebo after 2 weeks. They will then have a study visit every month up to end of month 6 when they will receive the 2nd dose of either the study drug or placebo. Other follow up visits will be conducted monthly until end of 12 months from the date of initial study drug or placebo dose. These follow-up visits will assess both safety and efficacy measures. Given new data showing that a higher dose might be needed to prevent malaria, a follow-on study will be done with consenting participants currently enrolled in part 2 who will receive an additional one or two doses of the study drug at a higher dose. Prior to this, a follow-on safety study will be done to look at these higher doses of L9LS to ensure they are safe and well tolerated. As part of the safety study, 24 children will be randomized to receive L9LS or placebo. They will then have another 10 study visits within a 3 months period to monitor various safety measures. If no safety signals are noted, then participants finishing part 2 will be consented for the follow-on study. For the follow-on study, participants who consent will be enrolled once they complete 12 months of follow-up for part 2. They will receive another antimalarial treatment course and two weeks later they will receive their third dose of either L9LS or placebo; six months later, they will receive a fourth dose of L9LS or placebo. Participants will get the same product (L9LS or placebo) that they received in part 2. They will continue to have monthly study visits until the end of the study (12 months following dose 3). These follow-up visits will assess both safety and efficacy measures. The study will provide information on the safety and usefulness of L9LS as a therapy used in the prevention of malaria. |
| Abstract of Study: |
Title: 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
Study 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. The primary study hypotheses are that L9LS will be safe and will produce protection against malaria infection. Before study agent administration, all subjects will be given dihydro-artemisinin-piperaquine (DP) to clear any preexisting Pf blood-stage infection.
Part 1: 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, we will administer the 5-mg/kg dose of L9LS or placebo 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, we will then administer a 20 mg/kg dose of L9LS or placebo 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, we will administer a 20-mg/kg dose of L9LS or placebo to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, we will move to part 2 of the trial. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. We will enroll 12 participants in each age-dose group in a 3:1 ratio of L9LS to placebo, and all participants will be followed for a total of 3 months.
Part 2: 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 care-seeking behavior questionnaires. Dosing will be based on three weight bands; all doses will be administered SC with fixed doses of 75 mg L9LS or 150 mg L9LS or a combination of the two (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.
Objectives:
Primary Objectives:
Part 1:
1. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children.
Part 2:
2. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-19 mg/kg by SC administration to healthy Kenyan children.
3. Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-19 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo.
Secondary Objectives:
1. To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo.
2. To assess the efficacy of one dose of L9LS at 10-19 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo.
3. To evaluate the efficacy of L9LS at 10-19 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo.
4. To assess protection of L9LS at 10-19 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo.
5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age.
6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age.
7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-19 mg/kg (part 2) in healthy Kenyan children, and
a. To correlate L9LS serum concentration with Pf infection risk.
b. To correlate L9LS serum concentration with clinical malaria risk.
Endpoints: Primary Endpoints:
1. Part 1 and Part 2: Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS, and incidence of serious adverse events (SAEs) throughout the study period.
2. Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood smear for 52 weeks after administration of L9LS or placebo.
Secondary Endpoints:
Data from one or both parts of this study will be used to assess the following endpoints:
1. Pf blood-stage infection as detected by microscopic examination of thick blood smear for 24 weeks after administration of L9LS or placebo.
2. Pf blood-stage infection as detected by RT-PCR for 24 and 52 weeks after administration of L9LS or placebo.
3. Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
4. Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
5. Measurement of L9LS in sera of recipients (parts 1 and 2).
6. PK analysis of L9LS and the association of L9LS concentration with Pf infection risk.
7. PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk.
Study Population: We will enroll a total of 396 healthy Kenyan children, including 72 ages 5 months to 10 years residing in western Kenya for part 1 and 324 ages 5-59 months for part 2.
|
| 1 |
Title: 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
Study 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 safety and 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. The primary study hypotheses are that L9LS will be safe and will produce protection against malaria infection. Before study agent administration, all subjects will be given dihydro-artemisinin-piperaquine (DP) to clear any preexisting Pf blood-stage infection.
Part 1: 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, we will administer the 5-mg/kg dose of L9LS or placebo 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, we will then administer a 20 mg/kg dose of L9LS or placebo 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, we will administer a 20-mg/kg dose of L9LS or placebo to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, we will move to part 2 of the trial. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. We will enroll 12 participants in each age-dose group in a 3:1 ratio of L9LS to placebo, for a total of 72 participants, and all participants will be followed for a total of 3 months.
Part 2: Efficacy study
A total of 324 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 care-seeking 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.
Objectives:
Primary Objectives:
Part 1:
1. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children.
Part 2:
2. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-20 mg/kg by SC administration to healthy Kenyan children.
3. Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-20 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo.
Secondary Objectives:
1. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo.
2. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo.
3. To evaluate the efficacy of L9LS at 10-20 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo.
4. To assess protection of L9LS at 10-20 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo.
5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age.
6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age.
7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-20 mg/kg (part 2) in healthy Kenyan children, and
a. To correlate L9LS serum concentration with Pf infection risk.
b. To correlate L9LS serum concentration with clinical malaria risk.
Endpoints:
Primary Endpoints:
1. Part 1 and Part 2: Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS, and incidence of serious adverse events (SAEs) throughout the study period.
2. Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood smear for 52 weeks after administration of L9LS or placebo.
Secondary Endpoints:
Data from one or both parts of this study will be used to assess the following endpoints:
1. Pf blood-stage infection as detected by microscopic examination of thick blood smear for 12 and 24 weeks after administration of L9LS or placebo.
2. Pf blood-stage infection as detected by RT-PCR for 24 and 52 weeks after administration of L9LS or placebo.
3. Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
4. Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
5. Measurement of L9LS in sera of recipients (parts 1 and 2).
6. PK analysis of L9LS and the association of L9LS concentration with Pf infection risk.
7. PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk.
Study Population: We will enroll a total of 396 healthy Kenyan children, including 72 ages 5 months to 10 years residing in western Kenya for part 1 and 324 ages 5-59 months for part 2.
Phase: 2
Description of Sites/Facilities Enrolling Participants: Study activities will take place at the KEMRI clinical trials unit based in the Siaya County Referral Hospital, which is the largest hospital in Siaya County, western Kenya. In part 2, study activities will also take place at Kogelo Dispensary, located approximately 12 km from Siaya County Referral Hospital.
Description of Study Intervention: Participants in part 1 of this study will receive one or two SC injections for a total dose of 5, 10, or 20 mg/kg of L9LS or placebo.
Participants in part 2 of this study will receive 10-20 mg/kg of L9LS or placebo as a single dose, given in 1 or 2 SC injections, depending on the total dose required. At 6 months after the initial injection, participants who received an initial dose of L9LS will either receive a second L9LS SC injection or a placebo injection. (Those in the placebo arm will receive a second injection of placebo.)
Study Duration: 24 months.
Participant Duration: 3 months (part 1) or 13 months (part 2).
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Title: 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
Study Description: A three-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 safety and protective efficacy of up to four 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, plus the safety and continued efficacy of a third and fourth dose of L9LS in a second year of follow-up. The primary study hypotheses are that L9LS will be safe and will produce protection against malaria infection. Before study agent administration, all subjects will be given dihydro-artemisinin-piperaquine (DP) to clear any preexisting Pf blood-stage infection.
Part 1: 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, we will administer the 5-mg/kg dose of L9LS or placebo 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, we will then administer a 20 mg/kg dose of L9LS or placebo to children aged 5-10 years and a 10-mg/kg dose of L9LS or placebo to children aged 5-59 months. If these doses are found safe after 1 week, we will administer a 20-mg/kg dose of L9LS or placebo to children aged 5-59 months. Should tolerability and safety of all doses be acceptable in children aged 5-59 months, we will move to part 2 of the trial. Dosing in part 1 of the study will be weight-based and all doses will be administered SC in a double-blinded fashion. We will enroll 12 participants in each age-dose group in a 3:1 ratio of L9LS to placebo, for a total of 72 participants, and all participants will be followed for a total of 3 months.
Part 1b: Age de-escalation and dose-escalation addition
Based on data from Mali suggesting that doses higher than 20mg/kg are needed to protect for 12 months, we propose to assess the safety of an additional two doses: 30 mg/kg and 40 mg/kg in a similar fashion. This extension of part 1 will include an additional 24 children, and will utilize a similar design to before, with 12 participants in each age-dose group in a 3:1 ratio of L9LS to placebo; all participants will be followed for a total of 3 months. However, given that it appears that the younger children are clearing the product more quickly than older people, we will include only children aged 5-71 months, as these are the ages of the children to be included in the part 2 extension. As before, we will ensure safety out to 7 days before proceeding to dose additional subjects.
Part 2: Efficacy study
A total of 324 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 care-seeking 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.
Part 2 extension: Assuming there are no safety signals from the day 7 review following dosing children with 30 and 40 mg/kg of product, and prior to the last study visit of the original protocol described above (September 2022 to June 2024), study participants who remain enrolled in the part 2 efficacy study will be invited to participate in a 12-month extension of the study. A separate written consent process will take place. Enrolled children will continue in the same study groups as in part 2: 1 dose L9LS, 2 doses L9LS, or placebo. A dose (of L9LS or placebo) will be given at the start of the extension and again after six months. Those receiving L9LS will receive a dose between 20 and 40 mg/kg, still in a double-blinded fashion. The monthly visit and sample collection schedule will mirror that in part 2.
Objectives:
Primary Objectives:
Part 1:
1. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 5 mg/kg, 10 mg/kg, and 20 mg/kg by SC administration to healthy Kenyan children.
Part 1b:
1. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 30 mg/kg and 40 mg/kg by SC administration to healthy Kenyan children
Part 2:
1. Safety: To evaluate the safety and tolerability of L9LS administered at doses of 10-20 mg/kg by SC administration to healthy Kenyan children.
2. Efficacy: To assess the efficacy of two doses of L9LS at a concentration of 10-20 mg/kg, administered SC to participants aged 5-59 months of age against first/only Pf malaria infection diagnosed by blood smear microscopy (irrespective of fever) over 12 months compared to placebo.
Secondary Objectives:
1. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 3 and 6 months compared to placebo.
2. To assess the efficacy of one dose of L9LS at 10-20 mg/kg against first/only Pf malaria infection diagnosed by blood smear microscopy over 12 months compared to placebo.
3. To evaluate the efficacy of L9LS at 10-20 mg/kg against first/only Pf malaria infection as detected by PCR over 6 and 12 months compared to placebo.
4. To assess protection of L9LS at 10-20 mg/kg against clinical malaria (first/only and all episodes) at 6 and 12 months compared to a placebo.
5. To assess the primary objective and secondary objectives 1-4 among children 5-17 months of age.
6. To assess the primary objective and secondary objectives 1-4 among children 18-59 months of age.
7. To evaluate the PK of L9LS throughout the study at weight-based dose levels of 5 mg/kg, 10 mg/kg, and 20 mg/kg (part 1) and fixed doses of 10-20 mg/kg (part 2) in healthy Kenyan children, and
a. To correlate L9LS serum concentration with Pf infection risk.
b. To correlate L9LS serum concentration with clinical malaria risk.
Part 2 Extension Primary Objectives
1. To evaluate the safety and tolerability of a third and fourth SC dose of L9LS at 20–40 mg/kg (compared to placebo) in healthy Kenyan children.
2. To evaluate the PK of L9LS throughout the follow-up phase at 20–40 mg/kg in healthy Kenyan children.
3. To determine if ADAs to L9LS can be detected in sera of recipients at specific timepoints throughout the study and to correlate the occurrence of ADAs with L9LS PK.
Part 2 Extension Exploratory Objectives (see Figure 4 for study arm definitions):
1. To assess the efficacy of a third and fourth SC dose of L9LS over one year at 20–40 mg/kg in mediating protection against Pf infection and clinical malaria in healthy Kenyan children during a second year of follow-up compared to those who received placebo only (arms 1 vs. 3; arms 2 vs. 3) and in those receiving two L9LS doses in the extension versus one (arms 1 vs. 2)
2. To evaluate the PK of L9LS throughout the study and to correlate L9LS serum concentration with Pf infection risk and clinical malaria risk
3. To evaluate the effect of a third and fourth dose of L9LS on development of acquired immunity (measured by antimalarial antibodies)
Endpoints: Primary Endpoints:
1. Part 1, part 1b, and part 2: Incidence and severity of local and systemic adverse events (AEs) occurring within 7 days after the administration of L9LS, and incidence of serious adverse events (SAEs) throughout the study period.
2. Part 2: Pf blood-stage infection as detected by microscopic examination of thick blood smear for 52 weeks after administration of L9LS or placebo.
Secondary Endpoints:
Data from one or both parts of this study will be used to assess the following endpoints:
1. Pf blood-stage infection as detected by microscopic examination of thick blood smear for 12 and 24 weeks after administration of L9LS or placebo.
2. Pf blood-stage infection as detected by RT-PCR for 24 and 52 weeks after administration of L9LS or placebo.
3. Incidence of clinical malaria (definition 1, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
4. Incidence of clinical malaria (definition 2, see section 2.2.2.3) for 24 and 52 weeks after administration of L9LS or placebo.
5. Measurement of L9LS in sera of recipients (parts 1 and 2).
6. PK analysis of L9LS and the association of L9LS concentration with Pf infection risk.
PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk.
Part 2 Extension Primary Endpoints:
1. Incidence and severity of local and systemic AEs occurring within 7 days after the administration of L9LS and incidence of serious adverse events (SAEs) throughout the study period.
2. Measurement of L9LS in sera of recipients.
3. Measurement of ADA in sera of recipients.
Part 2 Extension Exploratory Endpoints:
1. Pf blood-stage infection as detected by microscopic examination of thick blood smears obtained between 1 week and 52 weeks after administration of a third dose of L9LS or placebo.
2. Pf blood-stage infection as detected by RT-PCR from dried blood spots obtained between 1 week and 52 weeks after administration of a third dose of L9LS or placebo.
3. Incidence of clinical malaria (see section 2.2.2.3) between 1 week and 52 weeks after administration of a third dose of L9LS or placebo.
4. PK analysis of L9LS and the association of L9LS concentration with Pf infection risk.
5. PK analysis of L9LS and the association of L9LS concentration with clinical malaria risk.
6. Levels of naturally occurring antimalarial antibodies in participant blood at selected time points
Study Population: We will enroll a total of 396 healthy Kenyan children, including 72 ages 5 months to 10 years residing in western Kenya for part 1 and 324 ages 5-59 months for part 2.
The year 2 follow-on study will enroll an additional 24 children into an initial safety study (part 1b) and then participants who are currently enrolled in part 2 of the study and agree to continue in the extension phase will be followed for an additional year.
Phase: 2
Description of Sites/Facilities Enrolling Participants: Study activities will take place at the KEMRI clinical trials unit based in the Siaya County Referral Hospital, which is the largest hospital in Siaya County, western Kenya. In part 2 and the extension phase, study activities will also take place at Kogelo Dispensary, located approximately 12 km from Siaya County Referral Hospital.
Description of Study Intervention: Participants in part 1 of this study will receive one or two SC injections for a total dose of 5, 10, or 20 mg/kg of L9LS or placebo. Participants in part 1b will receive one or two SC injections for a total dose of 30 or 40 mg/kg.
Participants in part 2 of this study will receive 10-20 mg/kg of L9LS or placebo as a single dose, given in 1 or 2 SC injections, depending on the total dose required. At 6 months after the initial injection, participants who received an initial dose of L9LS will either receive a second L9LS SC injection or a placebo injection. (Those in the placebo arm will receive a second injection of placebo.)
In the part 2 extension study, the investigational product will be administered as two SC injection(s) of either L9LS at a dose of 20–40 mg/kg or matching placebo at the beginning of year 2 extension and after 6 months.
Study Duration: 36 months (including extension phase).
Participant Duration: 3 months (part 1or 1b) or 13 months (part 2) or 26 months (part 2 plus extension phase).
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