Trial to Evaluate CIS43LS in Healthy Adults

Phase 1CompletedNCT04206332

National Institute of Allergy and Infectious Diseases (NIAID)71 enrolled

Overview

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.

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.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 50 YearsHealthy volunteers:

Medical Language ↔ Plain English

* INCLUSION CRITERIA: 1. Able and willing to complete the informed consent process 2. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process 3. Available for clinical follow-up through the last study visit 4. 18 to 50 years of age 5. In good general health without clinically significant medical history 6. Physical examination without clinically significant findings within the 56 days prior to enrollment 7. Weight \<= 115 kg (for all groups except Groups 5, 10, and 16) and \< 100 kg for Group 15 8. Adequate venous access if assigned to an IV group or adequate subcutaneous tissue if assigned to an SC group 9. Willing to have blood samples collected, stored indefinitely, and used for research purposes 10. Agrees to participate in a controlled human malaria infection (CHMI) and to comply with post-CHMI follow-up requirements (except Group 4B) 11. Agrees to refrain from blood donation to blood banks for 3 years following participation in CHMI (except Group 4B) 12. Agrees not to travel to a malaria endemic region during the entire course of study participation Laboratory Criteria within 56 days prior to enrollment: 13. White Blood Cell (WBC) 2,500-12,000/mm\^3 14. WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval 15. Platelets = 125,000 - 500,000/mm\^3 16. Hemoglobin within institutional normal range or accompanied by the PI or designee approval 17. Creatinine \<= 1.1 x upper limit of normal (ULN) 18. Alanine aminotransferase (ALT) \<= 1.25 x ULN 19. Negative for HIV infection by an FDA approved method of detection Laboratory Criteria documented any time prior to enrollment: 20. Negative sickle cell screening test 21. Negative troponin test (except Group 4B) 22. Electrocardiogram (ECG) without clinically significant abnormalities (examples may include: pathologic Q waves, significant ST-T wave changes, left ventricular hypertrophy, any non-sinus rhythm excluding isolated premature atrial contractions, right or left bundle branch block, advanced A-V heart block). ECG abnormalities determined by a cardiologist to be clinically insignificant as related to study participation do not preclude study enrollment (except Group 4B) 23. No evidence of increased cardiovascular disease risk; defined as \>10% five-year risk by the non-laboratory method (except Group 4B) Criteria Specific to Women: 24. Postmenopausal for at least 1 year, post-hysterectomy or bilateral oophorectomy, or if of childbearing potential: 1. Negative beta-human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on day of enrollment, and prior to product administration and CHMI, and 2. Agrees to use an effective means of birth control through the duration of study participation * EXCLUSION CRITERIA: 1. Woman who is breast-feeding or planning to become pregnant during study participation 2. Previous receipt of a malaria vaccine 3. History of malaria infection 4. History of severe infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) defined per FDA guidance 5. Active SARS-CoV-2 infection 6. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis prior to enrollment that has a reasonable risk of recurrence during the study 7. Hypertension that is not well controlled 8. Receipt of any investigational study product within 28 days prior to enrollment (note: Emergency Use Authorization Coronavirus Disease 2019 (COVID-19) vaccine is not exclusionary) 9. Receipt of any live attenuated vaccines within 28 days prior to enrollment 10. Bleeding disorder diagnosed by a doctor (e.g. factor deficiency, coagulopathy, or platelet disorder requiring special precautions) or significant bruising or bleeding difficulties with intramuscular injections or blood draws 11. History of a splenectomy, sickle cell disease or sickle cell trait 12. History of skeeter syndrome or anaphylactic response to mosquito-bites (except Group 4B) 13. Known intolerance to chloroquine phosphate, atovaquone or proguanil (except Group 4B) 14. Use or planned use of any drug, including antibiotics, with antimalarial activity within 4 weeks prior to CHMI 15. History of psoriasis or porphyria, which may be exacerbated after treatment with chloroquine (except Group 4B) 16. Anticipated use of medications known to cause drug reactions with chloroquine or atovaquone-proguanil (Malarone) such as cimetidine, metoclopramide, antacids, and kaolin (except Group 4B) 17. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the volunteer, including but not limited to: diabetes mellitus type I, chronic hepatitis; OR clinically significant forms of: drug or alcohol abuse, asthma, autoimmune disease, psychiatric disorders, heart disease, or cancer

Outcomes

Primary Outcomes

Number of Participants Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration

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.

Time frame: 7 days after CIS43LS product administration, at approximately Week 1

Number of Participants Reporting Systemic Reactogenicity Signs and Symptoms Within 7 Days of CIS43LS Product Administration

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.

Time frame: 7 days after CIS43LS product administration, at approximately Week 1

Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following 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.

Time frame: Day 0 through 4 weeks after CIS43LS product administration

Number of Participants With One or More Unsolicited Non-Serious Adverse Events (AEs) Following Controlled Human Malaria Infection (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.

Time frame: Day 0 through 4 weeks after CHMI

Number of Participants With Serious Adverse Events (SAEs) Following CIS43LS Product Administration

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.

Time frame: Day 0 after CIS43LS product administration through the study participation, up to Week 24

Number of Participants With New Chronic Medical Conditions Following CIS43LS Product Administration

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.

Time frame: Day 0 after CIS43LS product administration through the study participation, up to Week 24

Number of Participants With Abnormal Laboratory Measures of Safety Following 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.

Time frame: Day 0 through 4 weeks after CIS43LS product administration

Secondary Outcomes

Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part A and Part B)

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.

Time frame: Baseline through 24 weeks after CIS43LS product administration

Pharmacokinetic (PK) Parameters of CIS43LS: Maximum Observed Serum Concentration (Cmax) - (Part C)

Time frame: Baseline through 24 weeks after CIS43LS product administration

Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part A and Part B)

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.

Time frame: Baseline through 24 weeks after CIS43LS product administration

Pharmacokinetic (PK) Parameters of CIS43LS: Time to Reach Maximum Observed Serum Concentration (Tmax) - (Part C)

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.

Time frame: Baseline through 24 weeks after CIS43LS product administration

Pharmacokinetic (PK) Parameters of CIS43LS: Beta Half-life (T1/2b) - (Part A and Part B)

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).

Trial to Evaluate CIS43LS in Healthy Adults

Overview

Conditions

Interventions

Eligibility

Locations (2)

Outcomes

Primary Outcomes

Secondary Outcomes