Malaria
Conditions
Brief summary
The purpose of this study is to assess the safety, tolerability, and pharmacokinetics of L9LS in infants in Mali and to evaluate the impact of L9LS on subsequent R21/Matrix-MTM vaccine immunogenicity.
Detailed description
This is an age-stratified, randomized, double-blind, placebo-controlled trial evaluating the safety, tolerability, and pharmacokinetics (PK) of one-time intramuscular (IM) administration of the monoclonal antibody (MAb) L9LS to healthy Malian infants aged 1 to 12 months, followed by an assessment of the impact of L9LS on the immunogenicity of subsequent administration of the R21/Matrix-MTM vaccine. The study hypotheses are that L9LS will be safe and will not impact the immunogenicity of the R21/Matrix-MTM vaccine. During the beginning of the 6-month malaria season (approximately August and September at the study site), 180 participants will be enrolled and randomized 1:1 to receive 150 mg of L9LS (n=90) or normal saline placebo (n=90). Randomization of participants in each arm will be age-stratified (1 to 4 months, n=60; \>4 to 8 months, n=60; \>8 to 12 months, n=60). The safety of L9LS will be assessed within each of the three (3) age strata. Participants will be followed at study visits 1, 3, 7, 14, 21, and 28 days later, and once every 4 weeks thereafter through study day 280 (40 weeks). Approximately 5 months after receiving L9LS or placebo, all participants will receive the R21/Matrix-MTM vaccine as 3 total doses given 4 weeks apart as per World Health Organization (WHO) recommendations and the anticipated Malian vaccination guidelines. Primary study assessments include medical history, physical examination, and blood collection to assess antibody responses to the R21/Matrix-MTM vaccine, L9LS PK, anti-drug antibody (ADA) assessments, identification of Plasmodium falciparum (Pf) infection by microscopic examination of thick blood smears and reverse transcription polymerase chain reaction (RT-PCR), and other research laboratory evaluations. Through their local provider, all participants 3 months and older will be offered 4 rounds of seasonal malaria chemoprevention (SMC) as a monthly 3-day treatment course of sulfadoxine-Pyrimethamine plus amodiaquine (SPAQ), as it is the standard of care in Mali for malaria prevention in children 3 months to 5 years of age.
Interventions
BIOLOGICALL9LS
Administered intramuscularly one time.
OTHERPlacebo
Normal Saline administered intramuscularly one time.
BIOLOGICALR21/Matrix-MTM
Administered intramuscularly as three total doses given four weeks apart on days 140, 168, 196.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health (NIH)
University of Washington
Harvard School of Public Health (HSPH)
Indiana University
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double-blind
Eligibility
Sex/Gender
ALL
Age
1 Months to 12 Months
Healthy volunteers
Yes
Inclusion criteria
1. Age ≥1 to ≤12 months at enrollment. 2. Born at ≥37 weeks gestation. 3. Parent and/or guardian able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process. 4. In good general health and without clinically significant medical history. 5. Parent and/or guardian able to provide informed consent. 6. Willing to have blood samples and data stored for future research. 7. Resides in or near Kalifabougou, Faladje, or Torodo, Mali, and available for the duration of the study.
Exclusion criteria
1. Body weight \<3.5 kg. 2. Behavioral, cognitive, or psychiatric disease in the parent and/or guardian that in the opinion of the investigator affects the ability of the parent and/or guardian to understand and comply with the study protocol. 3. Any fever (≥ 37.5°C, regardless of route) or acute illness within 7 days prior to randomization. 4. Clinically significant congenital anomaly or documented or suspected serious medical illness (e.g., history of epilepsy), serious congenital anomaly, or immediate life-threatening condition in the infant that may interfere with the ability to complete study requirements, as judged by the examining clinician. 5. Prior history of a suspected or actual acute life-threatening event. 6. Receipt of any blood products, monoclonal or polyclonal antibody/immunoglobulin (for example, hepatitis B immune globulin, intravenous immunoglobulin) or anticipated use during the study. 7. Any acute or chronic illnesses known in the mother during her pregnancy. 8. Parental study comprehension examination score of \<80% correct or per investigator discretion. 9. Hemoglobin, white blood cell (WBC), absolute neutrophil, or platelet count outside the local laboratory-defined limits of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.) 10. Alanine aminotransferase (ALT) or creatinine (Cr) level above the local laboratory-defined upper limit of normal. (Participants may be included at the investigator's discretion for "not clinically significant" values.) 11. Mother and/or infant infected with HIV. 12. Sickle cell disease by testing. (Note: Known sickle cell trait is NOT exclusionary.) 13. Evidence of clinically significant neurologic, cardiac, pulmonary, hepatic, endocrine, rheumatologic, autoimmune, hematological, oncologic, or renal disease by history, physical examination, and/or laboratory studies. 14. Receipt of any investigational product within the past 30 days. 15. Participation or planned participation in an interventional trial with an investigational product until the last required protocol visit. (Note: Past, current, or planned participation in observational studies is NOT exclusionary.) 16. History of a severe allergic reaction or anaphylaxis. 17. Salivary gland disorder diagnosed by a doctor (e.g., parotitis, sialadenitis, sialolithiasis, salivary gland tumors). 18. Pre-existing autoimmune or antibody-mediated diseases including but not limited to systemic lupus erythematosus or autoimmune thrombocytopenia. 19. Known immunodeficiency syndrome. 20. Known asplenia or functional asplenia. 21. 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. 22. Previous receipt of the R21/Matrix-MTM vaccine. 23. Previous receipt of an investigational malaria vaccine or monoclonal antibody. 24. Clinical signs of malnutrition. 25. Other condition(s) that, in the opinion of the investigator, would jeopardize the safety or rights of an individual participating in the trial, interfere with the evaluation of the study objectives, or render the participant unable to comply with the protocol.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Local Adverse Events (AEs) | Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0) | Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Local reactogenicity included pain/tenderness, swelling, redness, bruising, and pruritus at the site of infusion. Adverse events were captured by Investigator examination and history from participants. |
| Severity of Local Adverse Events (AEs) | Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0) | The severity of local AEs was graded using the Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Clinical Trials. Grade 1: Pain = does not interfere with activity; Tenderness = mild discomfort to touch; Erythema/Redness = 2.5-5 cm; Induration/Swelling = 2.5-5 cm and does not interfere with activity Grade 2: Pain = Repeated use of non-narcotic pain reliever \> 24 hours or interferes with daily activity; Tenderness=Discomfort with movement; Erythema/Redness = 5.1-10 cm; Induration/Swelling = 5.1-10 cm and interferes with activity Grade 3: Pain = Any use of narcotic pain reliever or prevents daily activity; Tenderness = Significant discomfort at rest; Erythema/Redness = \> 10 cm; Induration/Swelling = \> 10 cm or prevents daily activity Grade 4: Pain = Emergency room (ER) visit or hospitalization; Tenderness = ER visit or hospitalization; Erythema/Redness = Necrosis or exfoliative dermatitis; induration/Swelling = Necrosis Grade 5: Death |
| Participants With Systemic Adverse Events (AEs) | Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0) | Number of participants with local adverse events occurring within 7 days after administration of L9LS or placebo intervention. Systemic reactogenicity events included fever, feeling unusually tired or unwell, muscle aches, headache, chills, nausea, and joint pain. Adverse events were captured by Investigator examination and history from participants. |
| Severity of Systemic Adverse Events (AEs) | Within 7 days after administration of L9LS or matching Placebo intervention (administered on Day 0) | The severity of systemic AEs after the administration of L9LS or placebo was assessed using the grading scale below: Grade 1: Fever = 37.5\^oC-37.9\^oC; Fatigue, Headache, Myalgia = No interference with activity; Nausea = no interference with activity or 1-2 episodes/hour Grade 2: Fever = 38\^oC-38.4\^oC; Fatigue, Myalgia = Some interference with activity; Headache = Repeated use of non-narcotic pain reliever \> 24 hours or some interference with activity; Nausea = Some interference with activity or \> 2 episodes/24 hours Grade 3: Fever = 38.5\^oC-39.5\^oC; Fatigue = Prevents daily activity; Headache =Significant; any use of narcotic pain reliever or prevents daily activity; Myalgia =Significant; prevents daily activity; Nausea = Prevents daily activity, requires outpatient intravenous hydration Grade 4: Fever = \> 39.5\^oC; Fatigue, Headache, Myalgia = Emergency room (ER) visit or hospitalization; Nausea = ER visit or hospitalization for hypotensive shock Grade 5: Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Participants With Adverse Events of Special Interest (AESIs) Related to R21/Matrix-MTM Vaccine | Within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196) | Number of participants with Adverse events of special interest (AESIs), which is described as hypersensitivity reaction within seven days of receiving each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196). Adverse events of special interest (AESIs) are study-specific events that are of particular concern due to population, study intervention, class effect, etc. A Type III hypersensitivity reaction associated with the administration of the R21/Matrix-MTM vaccine are characterized by symptoms such as fever, arthralgia, myalgia, skin eruptions, lymphadenopathy, marked discomfort, and/or dyspnea. |
| Severity of Adverse Events of Special Interest (AESIs) | Within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196) | The severity of adverse events of special interest (AESIs) occurring within 7 days after administration of each dose of the R21/Matrix-MTM vaccine (administered on days 140, 168, 196) was graded using the table below. Participants with multiple episodes of same adverse event across grades were counted separately according to adverse event grade. Grade 1: Mild signs and symptoms Grade 2: Moderate signs and symptoms AND intervention indicated (e.g., antihistamines) Grade 3: Severe signs and symptoms AND higher level intervention indicated (e.g., steroids or IV fluids) Grade 4: Life-threatening consequences (e.g., requiring pressor or ventilator support) |
| Antibody Response to R21/Matrix-MTM Vaccine | Measured 28 days (Day 224) and 84 days (Day 280) after the third dose of R21/Matrix-MTM vaccination | The antibody response to the R21/Matrix-M was assessed as the total anti-Asn-Ala-Asn-Pro (anti-NANP) immunoglobulin G (IgG) ((anti-NANP IgG)) antibody titers. The total IgG anti-NANP antibody titers was measured by electrochemiluminescence immunoassay (ECLIA), using the Meso Scale Discovery LLC-based automation platform on serum samples collected 28 days (day 224) and 84 days (day 280) after the third dose of R21/Matrix-MTM vaccination. Outcomes analyzed as concentration of antibody titers of the polyclonal antibody response in a serum sample. Concentration is expressed in arbitrary units per milliliter (AU/mL), which are assigned based on a sample's relative binding as compared to an established serum reference standard. |
| Maximum Total Plasma Concentration (Cmax) for L9LS | Days 0 to 280 | Maximum total plasma concentration (Cmax) following a dose of 150 mg L9LS. Serum was collected on days 0, 7, 28, 84, 140, 196, and 280 after the administration of L9LS. Cmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles post dose. Analysis was done to determine each participant's maximum observed concentration based on all available data points and cumulative output was calculated as the central tendency and dispersion metric based on the observed maximum concentrations. |
| Time to Maximum Plasma Concentration (TMax) for L9LS | Days 0 to 280 | Time to maximum total plasma concentration (Tmax) following a dose of 150 mg or 300 mg L9LS. Serum was collected on days 0, 7, 28, 84, 140, 196, \& 280 after administration of L9LS. Tmax for L9LS was obtained directly by visual inspection of the plasma concentration versus time profiles. Analysis was done to determine the time (in days) at which the maximum observed concentration was achieved for each participant and cumulative output was calculated as the central tendency and dispersion metric based on the observed time of maximum concentration. |
| Area Under the Curve (AUC) for L9LS From Day 0 to 168 (AUC_168) | Days 0 to 280 | Plasma area under the concentration time curve (AUC) for L9LS from day 0 to day 168. Data for day 168 was interpolated using observed concentrations. Non-compartmental analysis was performed using the linear-up/log-down trapezoidal rule with the PKNCA package in R. |
| Area Under the Curve (AUC) From Day 0 to Last Observed for L9LS | Days 0 to 280 | The area under the concentration time curve from day 0 to the last observed concentration (in days) was calculated using the linear-up/log-down trapezoidal rule by non-compartmental analysis with the PKNCA package in R. |
| Area Under the Concentration Time Curve (AUC) From Day 0 to Infinity | Days 0 to 280 | The area under the concentration time curve (AUC) from day 0 to infinity, extrapolated from the last observed concentration, was calculated using the linear-up/log-down trapezoidal rule by non-compartmental analysis with the PKNCA package in R. |
| Terminal Half-life (t½) of L9LS | Days 0 to 280 | The terminal half-life was determined by non-compartmental analysis using the PKNCA package in R, which fits the natural logarithm of concentration by time using a minimum of four observed data points in the terminal phase, not including the maximum total plasma concentration (Cmax). |
Countries
Mali
Contacts
PRINCIPAL_INVESTIGATORPeter Crompton, MD, MPH
National Institutes of Health (NIH)
PRINCIPAL_INVESTIGATORKassoum Kayentao, MD, MPH, PhD
Faculté de Médecine Pharmacie d'Odontostomatologie (FMOS)
Participant flow
Pre-assignment details
327 participants were screened to participate in the study * 96 screen failure * 40 were backup * 11 participants withdrew prior to start of study * 180 participants were randomized One participant did not receive three doses of the R21/Matrix-MTM vaccine but completed the study
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 1-4 months | 60 Participants |
| Age, Customized 5-8 months | 60 Participants |
| Age, Customized 9-12 months | 60 Participants |
| Race/Ethnicity, Customized Black | 30 Participants |
| Region of Enrollment Mali | 30 participants |
| Sex: Female, Male Female | 15 Participants |
| Sex: Female, Male Male | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 30 | 1 / 30 | 0 / 30 | 0 / 30 | 0 / 30 | 0 / 30 | 0 / 177 |
| other Total, other adverse events | 30 / 30 | 30 / 30 | 30 / 30 | 30 / 30 | 30 / 30 | 30 / 30 | 83 / 177 |
| serious Total, serious adverse events | 1 / 30 | 1 / 30 | 0 / 30 | 0 / 30 | 2 / 30 | 0 / 30 | 0 / 177 |
Outcome results
None listed