Clinical trial NCT03478891: Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults
Official title: VRC 608: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy Adult Immune Responses to Vaccine
Keywords: Ebola Virus
Immune Response
Filovirus
Ebola Hemorrhagic Fever
First in Human
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2018-03-27
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: Background:

Ebola is a virus that has infected and killed people mostly in West Africa. There is no treatment or prevention for it, but several drugs are being studied. Researchers want to test the drug MAb114 in healthy people not exposed to Ebola to see whether it can be used for Ebola treatment in people who are infected in the future. This trial will not expose volunteers to the Ebola virus.

Objectives:

To see if MAb114 is safe and how a person's body responds to it.

Eligibility:

Healthy adults ages 18-60 who weigh 220.5 pounds or less

Design:

Participants will be screened under protocol NIH 11-I-0164 with:

* Medical history
* Physical exam
* Blood or urine tests

Participants will have a first 8- to10-hour visit. They will get MAb114 by IV infusion. For this, a thin tube will be placed in an arm vein. They may get an IV line in their other arm to collect blood. Blood will be taken many times before and after the infusion. Participants may have a urine test.

Participants will get a thermometer to check their temperature for 3 days after they get MAb114. They will record their highest temperature and any symptoms.

Participants will have about 14 more study visits over 6 months. At each visit, they will have blood taken and be checked for any health changes. They will talk about how they are feeling and if they have taken any medications.

At the end of the 6 months, participants may be invited to take part in another study for follow-up sample collection.

Detailed description: VRC 608: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-EBOMAB092-00-AB (MAb114), Administered Intravenously to Healthy Adults

Study Design: VRC 608 is the first-in-human Phase I study to examine safety, tolerability and pharmacokinetics of the monoclonal antibody (MAb), VRC-EBOMAB092-00-AB (MAb114). MAb114 will be administered as a single dose. The hypotheses are: 1) MAb114 administration to healthy adults will be safe by the intravenous (IV) route; and 2) MAb114 will be detectable in human sera with a definable half-life. The primary objectives are to evaluate the safety and tolerability of MAb114 in healthy adults. Secondary objectives will evaluate the pharmacokinetics of MAb114 and the potential to detect an anti-drug antibody response to MAb114.

Product Description: MAb114 is a human IgG1 MAb targeted to the Zaire ebolavirus (EBOV) glycoprotein (GP). It was developed by the VRC/NIAID/NIH and manufactured at Cook Pharmica LLC d.b.a. Catalent Indiana, LLC (Bloomington, IN) under current Good Manufacturing Practice (cGMP) regulations. MAb114 is supplied as a lyophilized product in a glass vial at 400 mg per vial with target overfill to 425 mg per vial.

Subjects: Up to 30 healthy adults, 18-60 years of age.

Study Plan: This is an open-label, dose-escalation study of MAb114 administered by IV infusion at dosages of 5, 25 and 50 mg/kg (Groups 1-3). Enrollment will begin with the lowest dose group. Following the first product administration in each group, the study team will wait at least 3 days before administering MAb114 to a second subject within the same group. Dose-escalation evaluations will occur to ensure the safety data support proceeding to the higher doses. Solicited reactogenicity following product administration will be evaluated using a 3-day diary. Assessment of safety will include clinical observation and monitoring of serum hematological and chemical parameters at defined timepoints throughout the study.

* Group 1: 3 subjects; 5 mg/kg IV
* Group 2: 5 subjects; 25 mg/kg IV
* Group 3: 10 subjects; 50 mg/kg IV
* Total\* 18 subjects

  * A minimum of 18 subjects will be enrolled. Enrollment up to a total of 30 subjects is permitted if additional subjects are necessary for safety or pharmacokinetic (PK) evaluations.

Study Duration: Subjects will be followed for 24 weeks after the study product administration.

Eligibility criteria: INCLUSION CRITERIA:

A volunteer must meet all of the following criteria:

* Able and willing to complete the informed consent process.
* Available for clinical follow-up through the last study visit.
* 18 to 60 years of age.
* In good general health without clinically significant medical history.
* Willing to have blood samples collected, stored indefinitely, and used for research purposes.
* Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
* Physical examination without clinically significant findings within the 84 days prior to enrollment.
* Have screening laboratory values within 84 days prior to enrollment that meet the following criteria:

  * White Blood Cell (WBC) 2,500-12,000/mm\^3
  * WBC differential either within institutional normal range or accompanied by the Principal Investigator (PI) or designee approval
  * Platelets = 125,000 - 400,000/mm\^3
  * Hemoglobin within institutional normal range or accompanied by the PI or designee approval
  * Creatinine less than or equal to 1.1 x upper limit of normal (ULN)
  * Alanine aminotransferase (ALT) less than or equal to 1.25 x ULN
  * Negative for human immunodeficiency virus (HIV) infection by a Food and Drug Administration (FDA) approved method of detection
  * Negative for Hepatitis B core antibody (HBcAb) and Hepatitis C virus antibody (HCV Ab)
* Criteria applicable to women of childbearing potential:

  * If a woman is of reproductive potential and sexually active with a male partner, then she agrees to use an effective means of birth control from the time of study enrollment until the last study visit, or to be monogamous with a partner who has had a vasectomy.
  * Negative human chorionic gonadotropin (beta-HCG) pregnancy test (urine or serum) on day of enrollment and product administration.

EXCLUSION CRITERIA:

A volunteer will be excluded from study participation if one or more of the following conditions apply:

* Previous receipt of a licensed or investigational monoclonal antibody or Ebola vaccine.
* Weight \>100 kg.
* 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.
* Hypertension that is not well controlled.
* Woman who is breast-feeding, or planning to become pregnant during study participation.
* Receipt of any investigational study product within 28 days prior to enrollment.
* 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.
* 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 (IM) injections or blood draws.
* Use of angiotensin-converting enzyme (ACE) inhibitors or other potential nephrotoxins.

Primary outcomes:
measure: Number of Subjects Experiencing Infusion Reaction During Product Administration
timeFrame: About 30 minutes of product administration
measure: Number of Subjects Reporting Systemic Reactogenicity Signs and Symptoms Within 3 Days of Product Administration
timeFrame: 3 days after product administration
measure: Number of Subjects Reporting Local Reactogenicity Signs and Symptoms Within 7 Days of Product Administration
timeFrame: 7 days after product administration
measure: Number of Subjects Reporting 1 or More Unsolicited Non-Serious Adverse Events
timeFrame: Through 24 weeks after product administration
measure: Number of Subjects Reporting Serious Adverse Events
timeFrame: Through 24 weeks after product administration
Secondary outcomes:
measure: Maximum Observed Serum Concentration (Cmax) of MAb114
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: Time to Reach Maximum Observed Serum Concentration (Tmax) of MAb114
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: Mean Serum Concentration of MAb114
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: Overall IV Half-life (T1/2) of MAb114
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-56 days post-infusion
measure: Area Under the Curve (AUC0-28D)
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: Volume of Distribution (Vd) at Steady-state
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: MAb114 Clearance Rate
timeFrame: Pre-infusion (baseline), end of infusion (0h), 1 hr, 3 hr, 6 hr, 24 hr, 48 hr and 7-28 days post-infusion
measure: Number of Subjects Who Produced Anti-drug Antibodies to MAb114
timeFrame: Days 28 and 56 post-infusion
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
name: Martin R Gaudinski, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Corti D, Misasi J, Mulangu S, Stanley DA, Kanekiyo M, Wollen S, Ploquin A, Doria-Rose NA, Staupe RP, Bailey M, Shi W, Choe M, Marcus H, Thompson EA, Cagigi A, Silacci C, Fernandez-Rodriguez B, Perez L, Sallusto F, Vanzetta F, Agatic G, Cameroni E, Kisalu N, Gordon I, Ledgerwood JE, Mascola JR, Graham BS, Muyembe-Tamfun JJ, Trefry JC, Lanzavecchia A, Sullivan NJ. Protective monotherapy against lethal Ebola virus infection by a potently neutralizing antibody. Science. 2016 Mar 18;351(6279):1339-42. doi: 10.1126/science.aad5224. Epub 2016 Feb 25.
citation: Misasi J, Gilman MS, Kanekiyo M, Gui M, Cagigi A, Mulangu S, Corti D, Ledgerwood JE, Lanzavecchia A, Cunningham J, Muyembe-Tamfun JJ, Baxa U, Graham BS, Xiang Y, Sullivan NJ, McLellan JS. Structural and molecular basis for Ebola virus neutralization by protective human antibodies. Science. 2016 Mar 18;351(6279):1343-6. doi: 10.1126/science.aad6117. Epub 2016 Feb 25.
citation: Gaudinski MR, Coates EE, Novik L, Widge A, Houser KV, Burch E, Holman LA, Gordon IJ, Chen GL, Carter C, Nason M, Sitar S, Yamshchikov G, Berkowitz N, Andrews C, Vazquez S, Laurencot C, Misasi J, Arnold F, Carlton K, Lawlor H, Gall J, Bailer RT, McDermott A, Capparelli E, Koup RA, Mascola JR, Graham BS, Sullivan NJ, Ledgerwood JE; VRC 608 Study team. Safety, tolerability, pharmacokinetics, and immunogenicity of the therapeutic monoclonal antibody mAb114 targeting Ebola virus glycoprotein (VRC 608): an open-label phase 1 study. Lancet. 2019 Mar 2;393(10174):889-898. doi: 10.1016/S0140-6736(19)30036-4. Epub 2019 Jan 24.