Trial to Evaluate CIS43LS in Healthy Adults
- Conditions
- Malaria
- Interventions
- Drug: VRC-MALMAB0100-00-ABOther: Plasmodium falciparum (P. falciparum) sporozoite challenge
- Registration Number
- NCT04206332
- Brief Summary
Background:
People get malaria when they are bitten by an infected mosquito. Malaria can be serious and sometimes deadly. Although there are medicines to treat malaria, there is no vaccine that fully prevents infection. Researchers want to test if an experimental drug can help.
Objective:
To test the safety and effectiveness of a drug called CIS43LS that could prevent malaria infection.
Eligibility:
Healthy people ages 18-50 who have never been infected with malaria
Design:
Participants were enrolled on the basis of eligibility criteria, evaluated by clinical laboratory tests, self-reported medical history, and physical examination.
Participants received CIS43LS either infused into a vein in their arm or injected into the fat under the skin. They were monitored for side effects for up to 4 hours after they received the drug. Participants received a thermometer and recorded their temperature and symptoms every day on/with/via a diary card for 7 days after administration. The administration site was checked for redness, swelling, itching or bruising.
Participants had up to 12 follow-up visits. At follow-up visits, participants had blood drawn and were checked for health changes or problems.
Most participants who received CIS43LS took part in a Controlled Human Malaria Infection Challenge (CHMI) along with control participants who did not receive CIS43LS. During the CHMI, mosquitoes carrying the malaria parasite bit participants in a controlled setting. The participants had clinic visits every day for up to 12 days starting 7 days after the CHMI. Participants were treated right away with antimalarial medication if they tested positive for malaria. Approximately 21 days after the CHMI, participants were treated with antimalarial medication for 3 days.
The study lasted 2-6 months depending on the participant's study group.
- Detailed Description
This was a multicenter, three-part, first-in-human, Phase 1, open-label, dose escalation study to evaluate the dose, safety, tolerability and protective efficacy of an anti-malaria human monoclonal antibody, VRC-MALMAB0100-00-AB (CIS43LS). The primary objective was to evaluate the safety and tolerability of CIS43LS when administered by either intravenous (IV) or subcutaneous (SC) routes. The secondary objectives were to evaluate the pharmacokinetics of CIS43LS at each dose level, determine if IV or SC administration will confer protection following a controlled human malaria infection (CHMI), and estimate the lowest protective dose of CIS43LS.
Part A: Part A evaluated the doses and routes in an open-label, dose escalation design.
Part B: Part B evaluated CIS43LS doses and routes prior to CHMI in participants previously enrolled in Part A and new Part B enrollees. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS dose intravenously. Additional participants were enrolled in Part B and received CIS43LS intravenously.
Part C: Part C evaluated CIS43LS doses and routes needed to reach a threshold of protection by assessing serum concentration prior to CHMI in a dose down design.
Study Product:
CIS43LS is a human immunoglobulin gamma-1 (IgG1) monoclonal antibody that was developed and manufactured by the National Institutes of Health (NIH) Vaccine Research Center (VRC). A recombinant Chinese hamster ovary DG44 clonal cell line14 developed by the Vaccine Production Program was transferred to the VRC pilot plant for clinical material manufacture. The study product was manufactured according to Good Manufacturing Practice at the VRC pilot plant operated by the Vaccine Clinical Materials Program, Leidos Biomedical Research (Frederick, MD, USA).
VRC-MALMAB0100-00-AB (CIS43LS) is a monoclonal antibody that recognizes a unique and conserved region of the Plasmodium falciparum (P. falciparum) circumsporozoite protein and incorporates an LS mutation to increase product half-life in plasma.
Participants:
A total of 71 participants enrolled in the study as follows:
Part A: 29 participants enrolled in Groups 1-5
Part B: 21\* participants enrolled in Groups 6-10
\*Out of the 21 Part B participants, 11 were newly enrolled and 10 were Part A participants who re-enrolled.
Of the 10 Part A participants who re-enrolled in Part B, 3 were back up participants who did not receive additional CIS43LS or CHMI and were terminated early because they were not needed.
Therefore, only 18 participants were actively enrolled in Part B: 11 newly enrolled and 7 Part A participants who re-enrolled.
Part C: 31 participants enrolled in Groups 11-16
Of the 71 participants enrolled, 47 participants received at least one dose of CIS43LS and 43 participants completed the CHMI.
Of the 47 participants who received CIS43LS, 4 participants who received a dose in Part A were also enrolled in Part B and received a second dose as follows:
* one participant received a 5 mg/kg IV dose in Part A and 20 mg/kg IV dose in Part B,
* one participant received a 5 mg/kg SC dose in Part A and 20 mg/kg IV dose in Part B, and
* two participants received a 20 mg/kg IV dose in Part A and Part B.
Therefore, a total of 51 doses of CIS43LS were administered to 47 participants as follows:
* 7 doses of 1 mg/kg IV
* 8 doses of 5 mg/kg SC
* 8 doses of 5 mg/kg IV
* 3 doses of 10 mg/kg IV
* 4 doses of 10 mg/kg SC
* 9 doses of 20 mg/kg IV and
* 12 doses of 40 mg/kg IV
Study Duration:
Participants who received CIS43LS were followed for up to 24 weeks after product administration. Control participants were followed through 7 weeks after CHMI.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 71
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Part A, Group 1: CIS43LS (5 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (5 mg/kg) administered by intravenous (IV) infusion (Day 0) Part A, Group 2: CIS43LS (5 mg/kg SC) VRC-MALMAB0100-00-AB CIS43LS (5 mg/kg) administered by subcutaneous (SC) injection (Day 0) Part A, Group 3: CIS43LS (20 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (20 mg/kg) administered by IV infusion (Day 0) Part A, Group 4A: CIS43LS (40 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (40 mg/kg) administered by IV infusion (Day 0) Part A, Group 4B: CIS43LS (40 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (40 mg/kg) administered by IV infusion (Day 0) Part B, Group 6: CIS43LS (5 mg/kg SC) VRC-MALMAB0100-00-AB CIS43LS (5 mg/kg) administered by SC injection (Day 0) Part B, Group 6: CIS43LS (5 mg/kg SC) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (5 mg/kg) administered by SC injection (Day 0) Part B, Group 7: CIS43LS (20 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (20 mg/kg) administered by IV infusion (Day 0) Part B, Group 7 participants included participants previously enrolled in Part A who received either 5 mg/kg IV (1), 5 mg/kg SC (1) or 20 mg/kg IV (2) in the first part of the study and newly enrolled Part B participants Part B, Group 7: CIS43LS (20 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (20 mg/kg) administered by IV infusion (Day 0) Part B, Group 7 participants included participants previously enrolled in Part A who received either 5 mg/kg IV (1), 5 mg/kg SC (1) or 20 mg/kg IV (2) in the first part of the study and newly enrolled Part B participants Part B, Group 8: CHMI [CIS43LS (40 mg/kg IV) in Part A] Plasmodium falciparum (P. falciparum) sporozoite challenge Part B, Group 8 participants included participants previously enrolled in Part A who received CIS43LS (40 mg/kg IV) in the first part of the study but did not receive CIS43LS in Part B of the study. Group 8 participants were enrolled to complete the controlled human malaria infection (CHMI). Part B, Group 9: CIS43LS (40 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (40 mg/kg) administered by IV infusion (Day 0) Part B, Group 9: CIS43LS (40 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (40 mg/kg) administered by IV infusion (Day 0) Part B, Group 10: CHMI Controls Plasmodium falciparum (P. falciparum) sporozoite challenge Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI) Part C, Group 11: CIS43LS (1 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (1 mg/kg) administered by IV infusion (Day 0) Part C, Group 11: CIS43LS (1 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (1 mg/kg) administered by IV infusion (Day 0) Part C, Group 12: CIS43LS (5 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (5 mg/kg) administered by IV infusion (Day 0) Part C, Group 12: CIS43LS (5 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (5 mg/kg) administered by IV infusion (Day 0) Part C, Group 13: CIS43LS (5 mg/kg SC) VRC-MALMAB0100-00-AB CIS43LS (5 mg/kg) administered by SC injection (Day 0) Part C, Group 13: CIS43LS (5 mg/kg SC) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (5 mg/kg) administered by SC injection (Day 0) Part C, Group 14: CIS43LS (10 mg/kg IV) VRC-MALMAB0100-00-AB CIS43LS (10 mg/kg) administered by IV infusion (Day 0) Part C, Group 14: CIS43LS (10 mg/kg IV) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (10 mg/kg) administered by IV infusion (Day 0) Part C, Group 15: CIS43LS (10 mg/kg SC) VRC-MALMAB0100-00-AB CIS43LS (10 mg/kg) administered by SC injection (Day 0) Part C, Group 15: CIS43LS (10 mg/kg SC) Plasmodium falciparum (P. falciparum) sporozoite challenge CIS43LS (10 mg/kg) administered by SC injection (Day 0) Part C, Group 16: CHMI Controls Plasmodium falciparum (P. falciparum) sporozoite challenge Control participants who did not receive CIS43LS and were enrolled to complete the controlled human malaria infection (CHMI)
- Primary Outcome Measures
Name Time Method Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following CIS43LS Product Administration Day 0 through 4 weeks after CIS43LS product administration Unsolicited adverse event (AE) data collection included AEs of all severities from the date of product administration through the Day 28 post-product administration visit. At other time periods between study product administration and when greater than 4 weeks after the study product administration, only serious AEs (SAEs reported as a separate outcome and in the AE module) and new chronic medical conditions that required ongoing medical management (reported as a separate outcome) were recorded through the last study visit. The relationship between an AE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.
Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration 7 days after CIS43LS product administration, at approximately Week 1 Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Local Symptom" is the number of participants reporting any local symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.
Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (CHMI) Day 0 through 4 weeks after CHMI Unsolicited adverse event (AE) data collection included AEs of all severities from CHMI through the Day 28 post-CHMI visit. The relationship between an AE and CHMI was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.
Number of Participants With New Chronic Medical Conditions Following CIS43LS Product Administration Day 0 after CIS43LS product administration through the study participation, up to Week 24 New chronic medical conditions that required ongoing medical management were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a new chronic medical condition and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.
Number of Participants With Abnormal Laboratory Measures of Safety Following CIS43LS Product Administration Day 0 through 4 weeks after CIS43LS product administration Abnormal laboratory results recorded as unsolicited adverse events (AEs) are summarized. Safety lab parameters included hematology (hemoglobin, hematocrit, mean corpuscular volume (MCV) platelets, and white blood cell (WBC), red blood cell (RBC), neutrophil, lymphocyte, monocyte, eosinophil and basophil counts) and chemistry (alanine aminotransferase (ALT) and creatinine). Complete Blood Count (CBC) with differential and Chemistry (ALT and creatinine) results were collected at different timepoints in Parts A, B and C throughout the study per the protocol's schedule of evaluations. Institutional laboratory normal ranges as well as the DAIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 were used.
Number of Participants With Serious Adverse Events (SAEs) Following CIS43LS Product Administration Day 0 after CIS43LS product administration through the study participation, up to Week 24 SAEs were recorded from receipt of first study product administration through the last expected study visit at Week 24. The relationship between a SAE and the study product was assessed by the investigator based on clinical judgment and the definitions outlined in the protocol. A participant with multiple experiences of the same event is counted once using the event of worst severity.
Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration 7 days after CIS43LS product administration, at approximately Week 1 Participants recorded the occurrence of solicited symptoms on a diary card for 7 days after study product administration and reviewed the diary card with clinic staff at a follow up visit. Participants were counted once for each symptom at the worst severity if they indicated experiencing the symptom more than one time at any severity during the reporting period. The number reported for "Any Systemic Symptom" is the number of participants reporting any systemic symptom at the worst severity. Reactogenicity grading (Mild, Moderate, Severe) was done using the U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and Infectious Diseases, Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1.
- Secondary Outcome Measures
Name Time Method Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part A and Part B) Baseline through 24 weeks after CIS43LS product administration Serum concentrations of CIS43LS by dose group following a single administration. Cmax is the peak serum concentration that CIS43LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group. After subcutaneous injection, Cmax could not be fully calculated because of COVID-19-related interruptions in sample collection.
Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge (Part B) Up to 21 days after CHMI Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine whether IV or SC administration of CIS43LS mediates protection against infectious P. falciparum following CHMI
Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part C) Baseline through 24 weeks after CIS43LS product administration Serum concentrations of CIS43LS by dose group following a single administration. Cmax is the peak serum concentration that CIS43LS achieves after it has been administered; it is determined as a maximum value on the summary pharmacokinetic (PK) curve for each study group.
Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part A and Part B) Baseline through 24 weeks after CIS43LS product administration Tmax is the time it takes to reach Cmax of CIS43LS after it has been administered; it is determined based on the summary PK curve for each dose group.
Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part C) Baseline through 24 weeks after CIS43LS product administration Tmax is the time it takes to reach Cmax of CIS43LS after it has been administered; it is determined based on the summary PK curve for each dose group.
Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part A and Part B) Baseline through 24 weeks after CIS43LS product administration Beta half-life (T1/2b) is being reported for this study. Beta half-life (T1/2b) is the time required for half of the CIS43LS product to be eliminated from the serum. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall beta half-life and bootstrap 90% confidence intervals (CIs).
Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part C) Baseline through 24 weeks after CIS43LS product administration Beta half-life (T1/2b) is the time required for half of the CIS43LS product to be eliminated from the serum. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall beta half-life and bootstrap 95% confidence intervals (CIs).
Pharmacokinetic (PK) Parameters of CIS43LS: Clearance Rate - (Part A and Part B) Baseline through 24 weeks after CIS43LS product administration Rate of CIS43LS elimination divided by the plasma CIS43LS concentration; determined based on the summary pharmacokinetic (PK) curve for each study group. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall clearance and bootstrap 90% confidence intervals (CIs).
Pharmacokinetic (PK) Parameters of CIS43LS: Clearance Rate - (Part C) Baseline through 24 weeks after CIS43LS product administration Rate of CIS43LS elimination divided by the plasma CIS43LS concentration; determined based on the summary pharmacokinetic (PK) curve for each study group. A two-compartmental population pharmacokinetic model with first order SC absorption was used to estimate overall clearance and bootstrap 95% confidence intervals (CIs).
Number of Participants Who Developed Plasmodium Falciparum (P. Falciparum) Parasitemia Following Controlled Human Malaria Infection (CHMI) Challenge (Part C) Up to 21 days after CHMI Parasitemia as determined by polymerase chain reaction (PCR) up to day 21 following CHMI to determine the lowest dose of CIS43LS administered IV and SC that confers protection against infectious P. falciparum following CHMI in Part C of the study
Trial Locations
- Locations (2)
University of Maryland Baltimore, Center for Vaccine Development
🇺🇸Baltimore, Maryland, United States
VRC Clinic, NIH Clinical Center
🇺🇸Bethesda, Maryland, United States