A COVID-19 Study to Evaluate Safety and PK of COVID-HIG Administered Through IM, SC, or IV Routes as a Single Dose Regimen to SARS-CoV-2 Uninfected Adults

A Phase 1, Open-Label, Randomized Study to Evaluate Safety and Pharmacokinetics of Anti-SARS-CoV-2 Immunoglobulin (Human) Investigational Product (COVID-HIG) Administered Through Intramuscular, Subcutaneous or Intravenous Routes as a Single Dose Regimen to SARS-CoV-2 Uninfected Adults

The primary objectives of this open-label trial were to evaluate the safety and pharmacokinetics (PK) of Anti-SARS-CoV-2 Immunoglobulin (Human) Investigational Product (COVID-HIG) administered intramuscularly (IM), subcutaneously (SC), or intravenously (IV) as a single dose in healthy adults 18-59 years of age with body mass index ≤35 kg/m^2. Prior studies examined IV administration, and the secondary objective of the present study was to compare PK among the three administration routes. No placebo group was included in the phase 1 randomized design. The exploratory objective was to evaluate disease severity in participants that became positive for SARS-CoV-2.

Study Overview

• Status: Completed
• Conditions: SARS-CoV-2 Infection
• Intervention / Treatment: Biological: COVID-HIG

Detailed Description

Eligible participants were randomized in two cohorts to receive COVID-HIG by IM, SC or IV in a 1:1:1 ratio and were stratified based on baseline SARS-CoV-2 IgG antibody status (low seropositive/seronegative; high seropositives were excluded). Up to 36 participants were planned to be enrolled and dosed in the study. A protocol amendment truncated the study to 23 randomized participants due to the impact of high circulating SARS-CoV-2 omicron cases on enrollment and participant retention. Participants were planned to be followed through Day 85 (approximately three half-lives), but the protocol was amended to shorten the study length to Day 57 due to timeline and PK considerations. The third substantial protocol amendment change was to remove the planned pseudovirus neutralization assay from the study due to its low sensitivity, limiting the PK analysis to the S-protein binding IgG immunoassay. PK time points included predose and postdose (from end of infusion/injection) 1 hr, 2 hr, 4 hr, 8 hr, 12 hr, Days 2, 3, 4, 6, 8, 15, 29, 43 and 57.

Nasopharyngeal swabs for SARS-CoV-2 were collected throughout the study. Per protocol, participants who became SARS-CoV-2 positive could not be assessed for PK at time points after testing positive, as the assay could not distinguish COVID-HIG from native antibodies. Participants who became SARS-CoV-2 positive during the study had disease severity assessed using an Ordinal Outcome Scale and followed via telemedicine through the end of the study.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Miami, Florida, United States, 33143
      • Qps-Mra, Llc
  • Missouri
    • Springfield, Missouri, United States, 65802
      • Bio-Kinetic Clinical Applications, LLC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

1. Able and willing to provide written informed consent (voluntarily signed by the participant) prior to performing study procedures.
2. Females and males 18-59 years of age.
3. Have a body mass index (BMI) less than or equal to 35.0 kg/m^2
4. Healthy, based on medical history (no chronic disease, no chronic therapy, no ongoing acute condition within four weeks prior to dosing), normal physical examination (no clinically significant findings in the opinion of the investigator), and screening laboratory assessments (no clinically significant findings in the opinion of the investigator).
5. No clinical symptoms suspicious for COVID-19 infection, as well as SARS-CoV-2 Immunoglobulin M (IgM) antibody negative and no laboratory evidence of current SARS-CoV-2 infection (i.e., reverse transcription polymerase chain reaction (RT-PCR) negative for SARS-CoV-2) at Screening.

6. Females must not be pregnant, or trying to become pregnant as demonstrated by either of the following A or B:

   A. Not of childbearing potential: surgically sterile (at least six weeks post bilateral salpingectomy, bilateral oophorectomy, or hysterectomy); or post-menopausal (history of ≥12 consecutive months without menses prior to randomization in the absence of other pathologic or physiologic causes and confirmed by follicle stimulating hormone [FSH] level ≥40 mIU/mL) OR

   B. Women of childbearing potential who are not planning to be pregnant during the study period who meet all of criteria i-iii:

   i. Negative serum pregnancy test at the Screening Visit. ii. Negative urine pregnancy test on Day 1 (a positive test will result in discontinuation from intervention).

   iii. Using one of the following highly effective methods of contraception during the study:

   1. Combined estrogen and progestogen, or progestogen-only hormonal contraception associated with inhibition of ovulation (e.g., implants, pills, patches) initiated ≥30 days prior to Study Day 1.
   2. Intrauterine device (IUD) or hormone releasing intrauterine system (IUS) inserted ≥30 days prior to Study Day 1.
7. Participant understands and agrees to comply with planned study procedures.

Exclusion Criteria:

1. Use of any investigational product within 30 days or SARS-CoV-2 monoclonal antibodies and COVID-19 convalescent plasma within 90 days prior to Screening or anticipated receipt during the study follow-up period, or participant plans to participate in another clinic study during the study period.
2. Receipt of 1 or 2 doses COVID-19 vaccine within 60 days prior to screening or during the study follow-up period.
3. SARS-CoV-2 IgG antibody levels >80 AU/mL as determined by the Diasorin LIAISON SARS-CoV-2 S1/S2 IgG antibody assay.
4. Screening clinical laboratory test result greater than the laboratory's upper limit of normal (ULN) for alanine aminotransferase (ALT), aspartate aminotransferase (AST), random glucose, total and/or direct bilirubin, blood urea nitrogen (BUN), or creatinine. Other serum chemistry parameters that are not within the reference range will not be considered exclusionary unless deemed clinically significant by the principal investigator.
5. Positive laboratory evidence of current infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis B virus (HBV). Note: Positive anti-HCV antibody result along with a negative HCV PCR would NOT be exclusionary.
6. History of allergy or hypersensitivity to blood or plasma products or to COVID-HIG excipients (proline, PS80).
7. History of allergy to latex or rubber.
8. History of hemolytic anemia.
9. History of Immunoglobulin A (IgA) deficiency.
10. Receipt of any blood product within the past 12 months.
11. Plasma donation within 7 days or blood loss/donation (>450 mL) within 56 days of dosing.
12. History of known congenital or acquired immunodeficiency or receipt of immunosuppressive therapy (e.g., prednisone or equivalent for more than two consecutive weeks within the past three months).
13. History of thrombosis or hypercoagulable state with increased risk of thrombosis.
14. Receipt of a live vaccine within 30 days prior to screening or anticipated receipt of a live vaccine during the study period.
15. Currently pregnant, breastfeeding, or planning to become pregnant during the study.
16. History of, or suspected substance abuse problem (including alcohol).
17. Any planned elective surgery or procedure during the follow-up period that impacts study compliance.
18. Other condition which may place participant at increased risk due to participation in the study or may impact study compliance as determined by the investigator.
19. An opinion of the investigator (or designee) that it would not be in the best interest of the individual to participate in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: COVID-HIG Intramuscular; Eligible subjects will be randomized to receive an 8.5mL dose of COVID-HIG by IM injections. COVID-HIG: COVID-HIG is a purified immunoglobulin G (IgG) liquid preparation containing antibodies (including neutralizing antibodies) to SARS-CoV-2.	Biological: COVID-HIG; Anti-SARS-CoV-2 Immunoglobulin (Human) [COVID-HIG] is a purified liquid immunoglobulin G (IgG) preparation; Other Names: NP-028
Experimental: COVID-HIG Subcutaneous; Eligible subjects will be randomized to receive an 8.5mL dose of COVID-HIG by SC injections. COVID-HIG: COVID-HIG is a purified immunoglobulin G (IgG) liquid preparation containing antibodies (including neutralizing antibodies) to SARS-CoV-2.	Biological: COVID-HIG; Anti-SARS-CoV-2 Immunoglobulin (Human) [COVID-HIG] is a purified liquid immunoglobulin G (IgG) preparation; Other Names: NP-028
Experimental: COVID-HIG Intravenous; Eligible subjects will be randomized to receive an 8.5mL dose of COVID-HIG by IV infusion. COVID-HIG: COVID-HIG is a purified immunoglobulin G (IgG) liquid preparation containing antibodies (including neutralizing antibodies) to SARS-CoV-2.	Biological: COVID-HIG; Anti-SARS-CoV-2 Immunoglobulin (Human) [COVID-HIG] is a purified liquid immunoglobulin G (IgG) preparation; Other Names: NP-028

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Participants With Adverse Events (AEs) up to 72 Hours Post-dosing	Number of participants with AEs and severity of AEs up to 72 hours post-dosing.	72 hours
Participants With Adverse Events That Led to Discontinuation or Temporary Suspension of Study Treatment	Number of participants and severity of AEs that led to discontinuation or temporary suspension of study treatment.	Day 1
Participants With AEs and SAEs After Study Treatment	Number of participants with adverse events (AEs) and serious adverse events (SAEs) up to 56 days post-administration of a single dose of COVID-HIG.	Day 0 to Day 57
Total Number of AEs and SAEs After Study Treatment	Number of adverse events (AEs) and serious adverse events (SAEs) in all participants reporting AEs/SAEs up to 56 days post-dosing.	Day 0 to Day 57
Pharmacokinetics Parameter of Area Under the Concentration-time Curve (AUC) From Time 0 to the Last Quantifiable Concentration (AUC0-last) of SARS-CoV-2 Antibodies After Dose of COVID-HIG	The area under the concentration-time curve from time 0 to the last quantifiable concentration of SARS-CoV-2 binding IgG antibodies after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetics Parameter of Area Under the Concentration-time (AUC) From Time 0 to Infinity (AUC0-inf) After Dose of COVID-HIGIV	Area under the concentration-time curve from time 0 to the last quantifiable concentration plus the additional area extrapolated to infinity of SARS-CoV-2 binding IgG antibodies after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetics Parameter of Maximum Observed Concentration (Cmax) of SARS-CoV-2 Antibodies Observed After Dose of COVID-HIG	The Cmax of SARS-CoV-2 binding IgG antibodies observed after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetics Parameter of Time at Which Cmax Occurs After Dose of COVID-HIG	Time at which Cmax occurs (Tmax) after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetics Parameter of Trough Concentration of SARS-CoV-2 Antibodies Observed 28 Days After Dose (Cmin28d) of COVID-HIG	The observed trough concentration of SARS-CoV-2 binding IgG antibodies 28 days after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, and Day 29.	Day 1 to Day 29

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics Parameter of Area Under the Concentration-time Curve (AUC) From Time 0 to 28 Days (AUC0-28d) After Dose of COVID-HIG.	AUC from time 0 to 28 days of SARS-CoV-2 binding IgG antibodies after COVID-HIG dose. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, and Day 29.	Day 1 to Day 29
Pharmacokinetics Parameter of Area Under the Concentration-time Curve (AUC) From Time 0 to 14 Days After Dose of COVID-HIG	AUC from time 0 to 14 days (AUC0-14d) of SARS-CoV-2 binding IgG antibodies after COVID-HIG. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, and Day 15.	Day 1 to Day 15
Pharmacokinetics Parameter of Apparent Terminal Elimination Half-life (T1/2) After Dose of COVID-HIG	The apparent terminal elimination half-life (T1/2) after dose of COVID-HIG. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetics Parameter of Systemic Clearance (CL) After Dose of COVID-HIG	The systemic clearance (CL) of SARS-CoV-2 binding IgG antibodies after dose of COVID-HIG. . Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57
Pharmacokinetic Parameter of Volume of Distribution (Vz) After Dose of COVID-HIG	The volume of distribution (Vz) of SARS-CoV-2 binding IgG antibodies after dose of COVID-HIG. Data for PK calculations was collected: pre-dose, and post-dose at: 1 hr, 2 hrs, 4 hrs, 8 hrs, 12 hrs, 24 hrs, Day 3, Day 4, Day 6, Day 8, Day 15, Day 29, Day 43, and Day 57.	Day 1 to Day 57

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparative Bioavailability: Area Under the Concentration-time Curve (AUC) From Time 0 to Last (AUC0-last) Ratios Between Administration Routes	AUC0-last ratios (bioavailability) compared between routes for comparable dose levels (COVID-HIG IM to SC; SC to IV; and IM to IV). Least square mean estimates and 90% confidence intervals were derived from ANOVA model with AUC0-last as dependent variable and administration route as fixed effect. Comparative bioavailability was defined as within [80%, 125%].	Day 1 to Day 57

Collaborators and Investigators

• Sponsor: Emergent BioSolutions
• Collaborators: United States Department of Defense
• Investigators: Study Director: Gideon Akintunde, MD, Emergent BioSolutions

Study record dates

Study Major Dates

• Study Start (Actual): December 7, 2021
• Primary Completion (Actual): March 28, 2022
• Study Completion (Actual): May 31, 2022

Study Registration Dates

• First Submitted: November 30, 2021
• First Submitted That Met QC Criteria: November 30, 2021
• First Posted (Actual): December 2, 2021

Study Record Updates

• Last Update Posted (Actual): June 20, 2024
• Last Update Submitted That Met QC Criteria: May 27, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: COVID-19; subcutaneous; Coronavirus disease 2019; Severe acute respiratory syndrome coronavirus 2; intravenous; intramuscular; immunoglobulins
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19
• Other Study ID Numbers: EBS-CVH-006

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No