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A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults

Primary Purpose

HIV Infections

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
PGDM1400/Placebo (3mg/kg IV)
PGDM1400/Placebo (10mg/kg IV)
PGDM1400/Placebo (30mg/kg IV)
PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV)
PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV)
PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV)
PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV)
PGDM1400 + PGT121 (MTD IV)
Sponsored by
International AIDS Vaccine Initiative
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for HIV Infections

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Groups 1 and 2 Inclusion Criteria:

  • HIV-uninfected males or females age 18-50 years old
  • Willing to maintain low risk behavior for HIV infection

Groups 1 and 2 Exclusion Criteria:

• Confirmed HIV-infection, pregnancy or lactation, significant acute or chronic disease and clinically significant laboratory abnormalities

Group 3 Inclusion Criteria:

  • HIV-infected males or females age 18-65 years old
  • Not on antiretroviral therapy with HIV-1 RNA plasma level between 1,000 and 100,000 copies/ml, CD4 cell count ≥ 300 cells/uL

Group 3 Exclusion Criteria:

• Significant acute or chronic medical condition other than HIV infection, and clinically significant laboratory abnormalities

Sites / Locations

  • Beth Israel Deaconess Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Group 1A HIV-Uninfected

Group 1B HIV-Uninfected

Group 1C HIV-Uninfected

Group 2A HIV-Uninfected

Group 2B HIV-Uninfected

Group 2C HIV-Uninfected

Group 3A HIV-infected off ART

Group 3B HIV-infected off ART

Arm Description

PGDM1400 low dose

PGDM1400 mid dose

PGDM1400 high dose

PGDM1400 + PGT121 low dose

PGDM1400 + PGT121 mid dose

PGDM1400 + PGT121 high dose

PGDM1400 + PGT121 + VRC07-523LS at 20mg/kg; HIV+ without ART

PGDM1400 + PGT121 at high dose; HIV + without ART

Outcomes

Primary Outcome Measures

Safety and tolerability
Proportion of participants with moderate or greater reactogenicity (e.g., solicited adverse events) for 3 days following IV infusion of PGDM1400 mAb alone, and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb Proportion of participants with adverse events (AEs), including safety laboratory (biochemical, hematological) parameters, during the first 56 days following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are moderate or greater, and/or related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb Proportion of participants with SAEs throughout the study period following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb
Elimination half-life (t1/2)
Elimination half-life following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Clearance (CL/F)
Clearance following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults.
Volume of distribution (Vz/F)
Volume of distribution following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Area under the concentration decay curve (AUC)
AUC following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Impact of viral load and/or ART
Impact of viral load and/or ART on PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb disposition
Antiviral activity of PGDM1400 in combination with PGT121 or PGDM1400 in combination with PGT121 and VRC07-523LS mAbs
Antiviral activity following IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, in viremic HIV-infected adults not on ART: Change in plasma HIV-1 RNA levels from baseline (mean of pre-entry and entry values)

Secondary Outcome Measures

Serum antibody titers against bNAbs
Serum anti-PGDM1400 antibody titers, Serum anti-PGT121 antibody titers and Serum anti-VRC07-523LS antibody titers
CD4+ T cell count
Determine if IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, has any impact on CD4+ T cell counts in HIV-infected adults. Change in CD4+ T cell count compared to baseline as measured by single platform flow cytometry
HIV genotyping of circulating virus
Compare plasma virus genotype activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART Genotypic analysis: Development of sequence variations in epitopes known to result in reduced PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization susceptibility or known to cause resistance to antiretroviral drugs
HIV phenotyping of circulating virus
Compare plasma virus phenotypic activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART. Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization.

Full Information

First Posted
May 12, 2017
Last Updated
September 11, 2020
Sponsor
International AIDS Vaccine Initiative
Collaborators
Beth Israel Deaconess Medical Center, Ragon Institute of MGH, MIT and Harvard, University of Texas Health, Houston AIDS Research Team (HART), Orlando Immunology Clinic
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1. Study Identification

Unique Protocol Identification Number
NCT03205917
Brief Title
A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults
Official Title
A Phase 1 Randomized Placebo-controlled Clinical Trial of the Safety, Pharmacokinetics and Antiviral Activity of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-uninfected and HIV-infected Adults
Study Type
Interventional

2. Study Status

Record Verification Date
September 2020
Overall Recruitment Status
Completed
Study Start Date
October 23, 2017 (Actual)
Primary Completion Date
April 20, 2020 (Actual)
Study Completion Date
April 20, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
International AIDS Vaccine Initiative
Collaborators
Beth Israel Deaconess Medical Center, Ragon Institute of MGH, MIT and Harvard, University of Texas Health, Houston AIDS Research Team (HART), Orlando Immunology Clinic

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400 and PGT121 and VRC07-523LS mAbs for HIV prevention and therapy.
Detailed Description
This is a Phase 1 study to evaluate the safety, tolerability, pharmacokinetics and anti-viral efficacy of the PGDM1400, PGT121 and VRC07-523LS mAbs for HIV prevention and therapy. PGDM1400, PGT121 and VRC07-523LS mAbs are recombinant human IgG1 monoclonal antibodies that target V1V2 (PGDM1400), a V3 glycan-dependent epitope (PGT121) and the CD4 binding site (VRC07-523LS) epitope region of the HIV envelope protein. PGT121, PGDM1400 and VRC07-523LS mAb were chosen for this study because of their potency, their ability to neutralize a wide array of cross-clade HIV viruses in a complementary pattern and their proven antiviral activity in animal studies e.g., their capacity to robustly prevent and treat simian-human immunodeficiency virus (SHIV) in rhesus monkeys.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
HIV Infections

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
29 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Group 1A HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 low dose
Arm Title
Group 1B HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 mid dose
Arm Title
Group 1C HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 high dose
Arm Title
Group 2A HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 + PGT121 low dose
Arm Title
Group 2B HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 + PGT121 mid dose
Arm Title
Group 2C HIV-Uninfected
Arm Type
Experimental
Arm Description
PGDM1400 + PGT121 high dose
Arm Title
Group 3A HIV-infected off ART
Arm Type
Experimental
Arm Description
PGDM1400 + PGT121 + VRC07-523LS at 20mg/kg; HIV+ without ART
Arm Title
Group 3B HIV-infected off ART
Arm Type
Experimental
Arm Description
PGDM1400 + PGT121 at high dose; HIV + without ART
Intervention Type
Biological
Intervention Name(s)
PGDM1400/Placebo (3mg/kg IV)
Intervention Description
3/1 (6/2 if DLT)
Intervention Type
Biological
Intervention Name(s)
PGDM1400/Placebo (10mg/kg IV)
Intervention Description
3/1 (6/2 if DLT)
Intervention Type
Biological
Intervention Name(s)
PGDM1400/Placebo (30mg/kg IV)
Intervention Description
3/1 (6/2 if DLT)
Intervention Type
Biological
Intervention Name(s)
PGDM1400 + PGT121/Placebo (3mg/kg + 3mg/kg IV)
Intervention Description
3/1 (6/2 if DLT)
Intervention Type
Biological
Intervention Name(s)
PGDM1400 + PGT121/Placebo (10mg/kg + 10mg/kg IV)
Intervention Description
3/1 (6/2 if DLT);
Intervention Type
Biological
Intervention Name(s)
PGDM1400 + PGT121/Placebo (30mg/kg + 30mg/kg IV)
Intervention Description
3/1 (6/2 if DLT)
Intervention Type
Biological
Intervention Name(s)
PGDM1400 + PGT121 + VRC07-523LS (20mg/kg + 20mg/kg + 20 mg/kg IV)
Intervention Description
3 (max 9)
Intervention Type
Biological
Intervention Name(s)
PGDM1400 + PGT121 (MTD IV)
Intervention Description
3 (max 9)
Primary Outcome Measure Information:
Title
Safety and tolerability
Description
Proportion of participants with moderate or greater reactogenicity (e.g., solicited adverse events) for 3 days following IV infusion of PGDM1400 mAb alone, and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb Proportion of participants with adverse events (AEs), including safety laboratory (biochemical, hematological) parameters, during the first 56 days following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are moderate or greater, and/or related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb Proportion of participants with SAEs throughout the study period following IV infusion of PGDM1400 mAb alone and a combination of PGDM1400 mAb and PGT121 mAb, and a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb, that are related to PGDM1400 mAb or PGT121 mAb or VRC07-523LS mAb
Time Frame
6 Months post infusion
Title
Elimination half-life (t1/2)
Description
Elimination half-life following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Time Frame
6 Months post infusion
Title
Clearance (CL/F)
Description
Clearance following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults.
Time Frame
6 months post infusion
Title
Volume of distribution (Vz/F)
Description
Volume of distribution following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Time Frame
6 months post infusion
Title
Area under the concentration decay curve (AUC)
Description
AUC following IV infusion of PGDM1400 mAb alone or a combination of PGDM1400 mAb and PGT121 mAb in HIV-uninfected and HIV-infected adults; or a combination of PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb in HIV-infected adults
Time Frame
6 months post infusion
Title
Impact of viral load and/or ART
Description
Impact of viral load and/or ART on PGDM1400 mAb and PGT121 mAb and VRC07-523LS mAb disposition
Time Frame
6 months post infusion
Title
Antiviral activity of PGDM1400 in combination with PGT121 or PGDM1400 in combination with PGT121 and VRC07-523LS mAbs
Description
Antiviral activity following IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, in viremic HIV-infected adults not on ART: Change in plasma HIV-1 RNA levels from baseline (mean of pre-entry and entry values)
Time Frame
6 Months post infusion
Secondary Outcome Measure Information:
Title
Serum antibody titers against bNAbs
Description
Serum anti-PGDM1400 antibody titers, Serum anti-PGT121 antibody titers and Serum anti-VRC07-523LS antibody titers
Time Frame
6 Months post infusion
Title
CD4+ T cell count
Description
Determine if IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb, has any impact on CD4+ T cell counts in HIV-infected adults. Change in CD4+ T cell count compared to baseline as measured by single platform flow cytometry
Time Frame
6 Months post infusion
Title
HIV genotyping of circulating virus
Description
Compare plasma virus genotype activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART Genotypic analysis: Development of sequence variations in epitopes known to result in reduced PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization susceptibility or known to cause resistance to antiretroviral drugs
Time Frame
6 Months post infusion
Title
HIV phenotyping of circulating virus
Description
Compare plasma virus phenotypic activity before and after IV infusion of PGDM1400 mAb in combination with PGT121 mAb, or PGDM1400 mAb in combination with PGT121 mAb and VRC07-523LS mAb to determine if PGDM1400 mAb and PGT121 mAb and/or PGT121VRC07-523LS mAb induced viral escape mutations have developed in viremic HIV-infected adults not on ART. Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization Phenotypic analysis: Changes in viral susceptibility to PGDM1400 mAb and/or PGT121 mAb and/or VRC07-523LS mAb neutralization.
Time Frame
6 months post infusion

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Groups 1 and 2 Inclusion Criteria: HIV-uninfected males or females age 18-50 years old Willing to maintain low risk behavior for HIV infection Groups 1 and 2 Exclusion Criteria: • Confirmed HIV-infection, pregnancy or lactation, significant acute or chronic disease and clinically significant laboratory abnormalities Group 3 Inclusion Criteria: HIV-infected males or females age 18-65 years old Not on antiretroviral therapy with HIV-1 RNA plasma level between 1,000 and 100,000 copies/ml, CD4 cell count ≥ 300 cells/uL Group 3 Exclusion Criteria: • Significant acute or chronic medical condition other than HIV infection, and clinically significant laboratory abnormalities
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Boris Juelg, MD, PhD
Organizational Affiliation
Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research, Ragon Institute of MGH, MIT and Harvard
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Kathryn Stephenson, MD, MPH
Organizational Affiliation
Beth Israel Deaconess Medical Center, Center for Virology and Vaccine Research
Official's Role
Study Chair
Facility Information:
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
35551291
Citation
Julg B, Stephenson KE, Wagh K, Tan SC, Zash R, Walsh S, Ansel J, Kanjilal D, Nkolola J, Walker-Sperling VEK, Ophel J, Yanosick K, Borducchi EN, Maxfield L, Abbink P, Peter L, Yates NL, Wesley MS, Hassell T, Gelderblom HC, deCamp A, Mayer BT, Sato A, Gerber MW, Giorgi EE, Gama L, Koup RA, Mascola JR, Monczor A, Lupo S, Rolle CP, Arduino R, DeJesus E, Tomaras GD, Seaman MS, Korber B, Barouch DH. Safety and antiviral activity of triple combination broadly neutralizing monoclonal antibody therapy against HIV-1: a phase 1 clinical trial. Nat Med. 2022 Jun;28(6):1288-1296. doi: 10.1038/s41591-022-01815-1. Epub 2022 May 12.
Results Reference
derived
Links:
URL
http://iavi.org
Description
IAVI Website

Learn more about this trial

A Clinical Trial of PGDM1400 and PGT121 and VRC07-523LS Monoclonal Antibodies in HIV-infected and HIV-uninfected Adults

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