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VRC 609 Study: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB091-00-AB (N6LS), Administered Intravenously or Subcutaneously With or Without Recombinant Human Hyaluronidase PH...

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03538626
Recruitment Status : Recruiting
First Posted : May 29, 2018
Last Update Posted : June 1, 2020
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Institute of Allergy and Infectious Diseases (NIAID) )

Brief Summary:

Background:

The experimental product in this study, N6LS, is a human monoclonal antibody. Antibodies are one way that the human body fights infection. Monoclonal means that all the antibodies in the product are the same. N6LS is directed against the HIV virus. There is no HIV in the N6LS study product and you cannot get HIV from this product. This study will be the first time N6LS is tested in humans. It will be given into a vein in your arm (intravenously, IV) or as an injection underneath your skin (subcutaneously, SC). The study will also test N6LS mixed with an enzyme, rHuPH20 (recombinant human hyaluronidase). rHuPH20 increases the spread of fluids injected underneath your skin (subcutaneously, SC) and allows for the rapid delivery of large volume injections that can be given with a single needle. It will be given as a SC infusion using a small needle attached to an infusion pump. Study products will only be given to healthy adults who are not infected with HIV.

Objective:

The main purpose of the study is to see if N6LS alone and N6LS mixed with rHuPH20 is safe in healthy adults. Another goal is to learn how amounts of N6LS in the body change over time.

You may be eligible to participate if you are:

  • 18 to 50 years old
  • Willing to get N6LS or N6LS with rHuPH20
  • Available for clinical follow-up for 6-11 months after enrollment
  • Willing to donate blood to be stored indefinitely for research use
  • In general good health

You will not be eligible to participate if you:

  • Have received a licensed or investigational monoclonal antibody in the past
  • Have a known sensitivity any ingredient in EDP
  • Weigh more than 253 pounds (115 kg)
  • Have HIV infection

Women must not be pregnant and must agree to use an effective method to prevent pregnancy during the entire study.

Study Plan:

32 to 40 healthy volunteers will be enrolled into 8 groups. Assigned study groups will depend on the dose of product, the numbers of times the product is given (once or three times at 12- week intervals), and how the product is given (IV or SC). Blood samples for research will be collected at most of the visits. There are about 14 clinic visits over 6 months for all groups getting one dose of product, and about 26 clinic visits over 12 months for the groups getting three doses of product. Participants will be compensated for their time and inconvenience.


Condition or disease Intervention/treatment Phase
HIV Antibodies Biological: VRC-HIVMAB091-00-AB Biological: EDP Phase 1

Detailed Description:

Study Design:

This is the first study in healthy adults of the N6LS monoclonal antibody (MAb). It is a dose-escalation study to examine safety, tolerability, dose, and pharmacokinetics (PK) of N6LS administered intravenously (IV) and subcutaneously (SC) to healthy adults. For SC administration, N6LS will be administered alone or coadministered with the permeation enhancer rHuPH20 enzyme. Primary hypotheses are that N6LS administration to healthy adults will be safe by the IV and SC routes, alone and with rHuPH20 coadministration. A secondary hypothesis is that all N6LS administrations will be detectable in human sera with a definable half-life

Product Description:

N6LS (VRC-HIVMAB091-00-AB ) is a human MAb targeted to the HIV-1 CD4 binding site. It was developed by the VRC/NIAID/NIH and manufactured under current Good Manufacturing Practice (cGMP) regulations at the VRC Vaccine Pilot Plant operated under contract by the Vaccine Clinical Materials Program (VCMP), Leidos Biomedical Research, Inc., Frederick, MD. The product is provided as a sterile aqueous buffered solution in 10 mL glass vials at a concentration of 100 mg/mL and volume of 6.25 mL.

Each vial of ENHANZE(TM) Drug Product (EDP) contains 0.5 mL of rHuPH20 formulated at a concentration of 1 mg/mL (approximately 110,000 U/mg rHuPH20). rHuPH20 is a tissue permeability modifier that depolymerizes hyaluronan (HA), increasing the dispersion of a substance into the subcutaneous space, which enables SC delivery of co-administered antibody (-ies) at higher dose volumes (e.g., >10 mL) that cannot be administered quickly without rHuPH20. EDP is manufactured by Ajinomoto Althea, Inc, (San Diego, CA) for Halozyme Therapeutics, Inc. (San Diego, CA) and is supplied in 2 mL glass vials as a sterile, single-dose, injectable liquid.

Subjects:

Healthy adults, 18-50 years of age.

Study Plan:

This open-label study includes 8 dose groups to assess N6LS alone given as a single IV infusion at the 5, 20, or 40 mg/kg dose level (Groups 1, 3,4); a single SC injection at the 5 mg/kg dose level (Group 2); or in 3 administrations, spaced 12 weeks apart by SC injection at the 5 mg/kg dose level (Group 5), or by IV infusion at the 20 mg/kg dose level (Group 6). Two additional groups will assess N6LS given as a single SC injection mixed with rHuPH20 (2000 U/mL) at 5 mg/kg (Group 7) or 20 mg/kg (Group 8) doses. Enrollment opened with Groups 1, 2 and 5; and was followed by the sequential activation of Groups 3, 4, and 6. With implementation of the two SC N6LS+ rHuPH20 arms as a protocol amendment, Group 7 will open first to accrual, followed by Group 8.

Study Duration:

Study participation will be approximately 24 weeks for subjects in Groups 1 to 4, 7 and 8; and 48 weeks for subjects in Groups 5 and 6.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: VRC 609: A Phase I, Open-Label, Dose-Escalation Study of the Safety and Pharmacokinetics of a Human Monoclonal Antibody, VRC-HIVMAB091-00-AB (N6LS), Administered Intravenously or Subcutaneously With or Without Recombinant Human Hyaluronidase PH20 (rHuPH20) to Healthy Adults
Actual Study Start Date : June 21, 2018
Estimated Primary Completion Date : December 31, 2020
Estimated Study Completion Date : December 31, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: 1
5 mg/kg IV x 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 2
5 mg/kg SC x 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 3
20 mg/kg IV x 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 4
40 mg/kg IV x 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 5
Smg/kg SC x 3
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 6
20mg/kg SC x 3
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Experimental: 7
Smg/kg SC and 2000U /ml X 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Biological: EDP
Recombinant human hyaluronidase PH20 (rHuPH20) enzyme optimizes the SC delivery of co# administered therapeutics by depolymerizing hyaluronan (HA) in the extracellular matrix of the SC space that normally serves to restrict bulk fluid flow. rHP40 is the active ingredient in ENHANZETM Drug Product (EDP).

Experimental: 8
20mg/kg SC and 2000U/ml x 1
Biological: VRC-HIVMAB091-00-AB
The N6LS antibody binds to the CD4- binding site of HIV-1 gp120 protein and contains a methionine to leucine (L) and asparagine to serine (S) (M428L/N434S, referred to as (LS) change within the C- terminus of the heavy chain constant region to increase its binding affinity for the neonatal Fc receptor (FcRn).

Biological: EDP
Recombinant human hyaluronidase PH20 (rHuPH20) enzyme optimizes the SC delivery of co# administered therapeutics by depolymerizing hyaluronan (HA) in the extracellular matrix of the SC space that normally serves to restrict bulk fluid flow. rHP40 is the active ingredient in ENHANZETM Drug Product (EDP).




Primary Outcome Measures :
  1. To evaluate the safety and tolerability of a single 5 or 20 mg/kg SC dose of N6LS coadministered with rHuPH20 in healthy adults [ Time Frame: Day 0 to week 24 ]
    Product is safe and tolerable

  2. To evaluate the safety and tolerability of N6LS administered as a single dose at 5 mg/kg IV, 20 mg/kg IV, 40 mg/kg IV, or 5 mg/kg SC to healthy adults. [ Time Frame: Day O to week 24 ]
    Product is safe and tolerable

  3. To evaluate the safety and tolerability of N6LS administered at 5 mg/kg SC or 20 mg/kg IV by repeat dosing every 12 weeks for a total of 3 injections/infusions in healthy adults. [ Time Frame: Day 0 to week 48 ]
    Product is safe and tolerable


Secondary Outcome Measures :
  1. To evaluate the pharmacokinetics of N6LS at each dose level through 24 weeks after the last dose. [ Time Frame: Day 0 to week 24 ]
    Determine pharmacokinetics of N6LS

  2. To determine whether anti-drug antibody (ADA) to N6LS can be detected in sera of N6LS recipients atbaseline, 4-weeks post each product administration, and at the last study visit. [ Time Frame: Day 0 to week 48 ]
    To determine whether antidrug antibody to N6LS can be detected in serum



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria
  • INCLUSION CRITERIA:

A subject must meet all of the following criteria:

  1. Willing and able to complete the informed consent process.
  2. 18 to 50 years of age.
  3. Based on history and examination, must be in good general health and without history of any of the conditions listed in the exclusion criteria.
  4. Willing to have blood samples collected, stored indefinitely, and used for research purposes.
  5. Able to provide proof of identity to the satisfaction of the study clinician completing the enrollment process.
  6. Screening laboratory criteria within 84 days prior to enrollment must meet the following criteria:

    • White blood cell count (WBC): 2,500-12,000/mm(3).
    • WBC differential: 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 PI or designee approval.
    • Creatinine: less than or equal to 1.1 x Upper Limit of Normal (ULN).
    • ALT: less than or equal to 1.25 x ULN.
    • AST: less than or equal to 1.25 x ULN.
    • Negative for HIV infection by an FDA approved method of detection.

    Female-Specific Criteria:

  7. 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.
  8. Negative beta-HCG (human chorionic gonadotropin) pregnancy test (urine or serum) on day of enrollment for women presumed to be of reproductive potential.

EXCLUSION CRITERIA:

A subject will be excluded if one or more of the following conditions apply:

  1. Prior receipt of licensed or investigational monoclonal antibody.
  2. Weight > 115 kg.
  3. Any history of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis within the 2 years prior to enrollment that has a reasonable risk of recurrence during the study.
  4. Hypertension that is not well controlled.
  5. Woman who is breast-feeding, or planning to become pregnant during the study participation.
  6. Receipt of any investigational study agent within 28 days prior to enrollment.
  7. Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the subject 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.
  8. Known hypersensitivity to hyaluronidase or any of the excipients in EDP.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03538626


Contacts
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Contact: VRC Clinic (301) 451-8715 vaccines@nih.gov

Locations
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United States, Maryland
National Institutes of Health Clinical Center Recruiting
Bethesda, Maryland, United States, 20892
Contact: VRC Clinic    301-451-8715    vaccines@nih.gov   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
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Principal Investigator: Martin R Gaudinski, M.D. National Institute of Allergy and Infectious Diseases (NIAID)
Additional Information:
Publications:

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Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03538626    
Other Study ID Numbers: 180105
18-I-0105
First Posted: May 29, 2018    Key Record Dates
Last Update Posted: June 1, 2020
Last Verified: May 21, 2020

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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) ):
Immune Cells
bNAb
Plasma Cell
HIV
Immunotherapy