Safety, Tolerability, and Pharmacokinetics of SAB-301 in Healthy Adults

• ClinicalTrials.gov Identifier: NCT02788188
• Recruitment Status: Completed
• First Posted: June 2, 2016
• Results First Posted: June 12, 2018
• Last Update Posted: June 12, 2018
• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
• Collaborators: Naval Medical Research Center; SAb Biotherapeutics, Inc.
• Information provided by (Responsible Party): National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Study Description

Brief Summary:

Background:

Middle East Respiratory Syndrome (MERS) is a newly discovered contagious and sometimes fatal respiratory virus. People often get MERS through close contact with an infected person. Scientists are worried that MERS may spread and cause more infections. There are no vaccines or treatments for MERS right now. Researchers think a new therapy called SAB-301 may be able to help. Antibodies are proteins the body makes to attack viruses. SAB-301 is made of antibodies made in cows to fight MERS. The antibodies are collected from plasma, the liquid part of cow blood.

Objective:

To evaluate the safety and tolerability of SAB-301 in healthy adults.

Eligibility:

Healthy people ages 18 60 who:

Do not have chronic medical problems

Do not take any medications (exceptions are acetaminophen, ibuprofen, vitamins, seasonal allergy meds and oral contraception)

Do not have allergies to beef products

Agree to use two forms of contraception while on study (both men and women)

Design:

Participants will be screened with:

Medical history

Physical examination

Blood and urine tests

Participants will have a return visit.

They will have a physical exam and blood tests.

They will be randomly assigned to receive either SAB-301 or a placebo which is given by infusion

through an arm vein over 1 3 hours.

They will be monitored at the clinic for 6 hours after the infusion. They will have additional blood draws.

Participants will have 2-hour visits 1, 3, 7, 21, 42, and 90 days after the infusion. At each visit they will be evaluated and have blood and urine tests.

Condition or disease	Intervention/treatment	Phase
Middle East Respiratory Syndrome Coronavirus	Biological: SAB-301; Other: Normal (9%) Saline	Phase 1

Detailed Description:

The administration of convalescent plasma or hyperimmune immunoglobulin is often used for treatment of emerging infectious diseases. However, production of large quantities of anti-pathogen human plasma and/or immunoglobulin with high affinity and avidity antibodies currently requires donations by convalescent humans, a process that can limit availability for a number of reasons. One novel alternative source is transchromosomic (Tc) cattle that produce fully human polyclonal IgG (hIgG) de novo and mount a robust antibody immune response after vaccination.

This study will evaluate the safety, tolerability, and immunogenicity of SAB-301, a fully human polyclonal anti-MERS IgG collected from transchromosomic cattle. Beginning with a low single-dose, subjects are randomized to receive either SAB-301 or a normal saline control, and evaluated on Study Days 1, 3, 7, 21, 42, and 90. The safety and tolerability is evaluated using symptoms, clinical laboratory tests, pharmacokinetics, and immunogenicity assays. Utilizing a series of stopping rules and a medical monitor, the dose will be escalated as safety and tolerability are established.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 38 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Randomized Double-Blind, Placebo-Controlled, Single Ascending Dose Safety, Tolerability, and Pharmacokinetics Study of SAB-301 in Healthy Adults
• Study Start Date: May 28, 2016
• Actual Primary Completion Date: April 10, 2018
• Actual Study Completion Date: April 30, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Cohort 1; Cohort 1: 1mg/kg SAB-301 in normal (9%) saline; concentration 1mg/mL (0.1%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Placebo Comparator: Placebo; Normal (0.9%) saline in approximately the same volume as each cohort in the experimental drug arm.	Other: Normal (9%) Saline; Normal (0.9%) saline in approximately the same volume as each cohort in the experimental drug arm.
Experimental: Cohort 2; Cohort 2: 2.5 mg/kg SAB-301 in normal (9%) saline; concentration 1mg/mL (0.1%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 3; Cohort 3: 5mg/kg SAB-301 in normal (9%) saline; concentration 4mg/mL (0.4%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 4; Cohort 4: 10mg/kg SAB-301 in normal (9%) saline; concentration 4mg/mL (0.4%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 5; Cohort 5: 20mg/kg SAB-301 in normal (9%) saline; concentration 20mg/mL (2%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.
Experimental: Cohort 6; Cohort 6: 50mg/kg SAB-301 in normal (9%) saline; concentration 20mg/mL (2%)	Biological: SAB-301; SAB-301 is a purified human immune globulin G (hIgG) polyclonal antibody designed to specifically bind to the MERS-CoV spike (S) protein, a component of the virion membrane that is responsible for binding of the virus to the host cell. The hIgG is purified from the plasma of immunized transchromosomic (Tc) bovines that were immunized with a recombinant spike protein produced in insect cells. SAB-301 is purified hIgG in a sterile liquid formulated in 10 mM glutamic acid monosodium salt, 262 mM D-sorbitol, 0.05 mg/mL Tween 80, pH 5.5. The drug product will be administered intravenously and will be diluted in saline per the clinical protocol.

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Having Adverse Events [ Time Frame: 90 days ]
   Number of participants who experienced an adverse event

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

• INCLUSION CRITERIA:

  1. Age greater than or equal to 18 years and less than or equal to 60 years
  2. Body mass index (BMI) of 19-32 kg/m(2)
  3. Estimated glomerular filtration rate greater than or equal to 70 mL/min at screening, calculated using the CKD-EPI formula
  4. Subjects must agree to:

• Not take any prescription or OTC medications with the exception of acetaminophen, ibuprofen, vitamins, seasonal allergy medications, and/or contraceptive medications for a period 7 days prior to study drug administration (i.e., Day 0)

  5. One of the following in order to avoid pregnancy:

• Females who are able to become pregnant (i.e., are not postmenopausal, have not undergone surgical sterilization, and are sexually active with men) must agree to use at least 2 effective forms of contraception from the date of the subject s signing of the informed consent form through 60 days after the last dose of study drug. At least one of the methods of contraception should be a barrier method.
• Males who have not undergone surgical sterilization and are sexually active with women must agree to use condoms plus have a partner use at least one additional effective form of contraception from the date of the subject s signing of the informed consent form through 60 days after the last dose of study drug.

EXCLUSION CRITERIA:

1. Any history of allergy, anaphylaxis, or severe reaction to beef products (including milk and gelatin)
2. Any history of allergy, anaphylaxis, or severe reaction to IGIV or human blood products
3. Any chronic medical problem that requires daily oral medications (except Tylenol, ibuprofen, oral contraceptives, vitamins, and seasonal allergy medications).
4. History of cardiovascular disease, cardiomyopathy, heart failure, or unexplained syncope
5. Subjects that have had confirmed MERS
6. Women who are breast-feeding
7. Positive urine or serum pregnancy test

8. Abnormal chemistry panel

   -defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table

   --evaluating only sodium (Na), potassium (K), serum bicarbonate (total CO2), blood urea nitrogen (BUN), creatinine, glucose, asp (ALT), aspartate aminotransferase (AST), total bilirubin, lactate dehydrogenase (LDH), and estimated glomerular filtration rate (GFR) by the CKD-EPI equation.

9. Abnormal complete blood count (CBC)

   -defined as any clinically significant baseline Grade 1 or greater toxicity, or any Grade 3 or greater toxicity (regardless of clinical significance) by the toxicity table--evaluating only the WBC (to include absolute neutrophil, lymphocyte, and eosinophil counts), hemoglobin, hematocrit, and platelets.

10. Abnormal urinalysis

    -defined as any clinically significant baseline Grade 1 or greater toxicity--evaluating only protein, and RBCs

11. Positive rheumatoid factor
12. IgA deficiency (defined as IgA < 7 mg/dL)
13. Participation in another research study with receipt of any investigational drug within 5 half-lives or 30 days, whichever is longer, prior to study drug administration (i.e., Day 0) and until completion of the study
14. Participation in any other research study for 30 days after study drug administration
15. Receipt of blood products within 2 months prior to study drug administration (i.e. Day 0)
16. Receipt of any vaccination within 30 days prior to study drug administration (i.e. Day 0)
17. Any acute or chronic condition that, in the opinion of the Investigator, would limit the subject s ability to complete and/or participate in this clinical study

Contacts and Locations

Locations

United States, Maryland

National Institutes of Health Clinical Center

Bethesda, Maryland, United States, 20892

Sponsors and Collaborators

National Institute of Allergy and Infectious Diseases (NIAID)

Naval Medical Research Center

SAb Biotherapeutics, Inc.

Investigators

• Principal Investigator: Richard T Davey, M.D.; National Institute of Allergy and Infectious Diseases (NIAID)

  Study Documents (Full-Text)

Documents provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

Study Protocol and Statistical Analysis Plan  [PDF] November 1, 2016

More Information

Additional Information:

NIH Clinical Center Detailed Web Page 

Publications of Results:

Beigel JH, Voell J, Kumar P, Raviprakash K, Wu H, Jiao JA, Sullivan E, Luke T, Davey RT Jr. Safety and tolerability of a novel, polyclonal human anti-MERS coronavirus antibody produced from transchromosomic cattle: a phase 1 randomised, double-blind, single-dose-escalation study. Lancet Infect Dis. 2018 Apr;18(4):410-418. doi: 10.1016/S1473-3099(18)30002-1. Epub 2018 Jan 9.

Other Publications:

Luke T, Wu H, Zhao J, Channappanavar R, Coleman CM, Jiao JA, Matsushita H, Liu Y, Postnikova EN, Ork BL, Glenn G, Flyer D, Defang G, Raviprakash K, Kochel T, Wang J, Nie W, Smith G, Hensley LE, Olinger GG, Kuhn JH, Holbrook MR, Johnson RF, Perlman S, Sullivan E, Frieman MB. Human polyclonal immunoglobulin G from transchromosomic bovines inhibits MERS-CoV in vivo. Sci Transl Med. 2016 Feb 17;8(326):326ra21. doi: 10.1126/scitranslmed.aaf1061.

Steinberger BA, Ford SM, Coleman TA. Intravenous immunoglobulin therapy results in post-infusional hyperproteinemia, increased serum viscosity, and pseudohyponatremia. Am J Hematol. 2003 Jun;73(2):97-100. doi: 10.1002/ajh.10325.

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT02788188
• Other Study ID Numbers: 160119; 16-I-0119
• First Posted: June 2, 2016
• Results First Posted: June 12, 2018
• Last Update Posted: June 12, 2018
• Last Verified: July 2017

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) ):

First in Human; Middle East Respiratory Syndrome (MERS); Tc Bovine-Derived; Transchromosomic Cattle

Additional relevant MeSH terms:

Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections