Evaluation of Trimer 4571 Therapeutic Vaccination in Adults Living With HIV on Suppressive Antiretroviral Therapy (NETI)

• ClinicalTrials.gov Identifier: NCT04985760
• Recruitment Status: Recruiting
• First Posted: August 2, 2021
• Last Update Posted: April 12, 2022
• Sponsor: Madhu Chhanda Choudhary
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID)
• Information provided by (Responsible Party): Madhu Chhanda Choudhary, University of Pittsburgh

Study Description

Brief Summary:

Trimer 4571 is a vaccine designed to stimulate the development of broadly neutralizing antibodies (bnAbs) against HIV. Trimer 4571 is investigational, meaning it is not approved by the US Food and Drug Administration (FDA). There is limited human experience with the Trimer 4571 vaccine administered with aluminum hydroxide (alum) and the vaccine has not been tested in people with HIV prior to this study although it has been tested in healthy volunteers. The goal of this study is to see if Trimer 4571 is safe and well tolerated and to see if it will help the immune system produce bnAbs against HIV.

Condition or disease	Intervention/treatment	Phase
HIV Infections	Biological: Trimer 4571 vaccine 100mcg with 500mcg alum adjuvant; Biological: Placebo control for Trimer 4571 vaccine 100mcg with 500mcg alum adjuvant; Biological: Trimer 4571 vaccine 500mcg with 500mcg alum adjuvant; Biological: Placebo control for Trimer 4571 vaccine 500mcg with 500mcg alum adjuvant	Phase 1

Detailed Description:

The immune system is composed of special cells, proteins, tissues, and organs that protect against germs and microorganisms and is the body's defense against infections. Antibodies are a type of protein that helps the body fight infection and are usually made by a person's own immune system. A type of antibody that can recognize and block many types of HIV from entering healthy cells are called broadly neutralizing antibodies, or 'bnAbs', and may also activate other immune cells to help destroy HIV-infected cells. Research has shown that people with HIV who develop bnAbs against the virus are better able to control the infection. While the immune systems of some people with HIV show signs of early bnAb production, only a small percentage of people with HIV naturally develop bnAbs.

Approximately 32 participants will be sequentially enrolled and randomized 3:1 by chance like rolling dice to receive either the Trimer 4571 vaccine or a placebo vaccine that does not contain Trimer 4571.

Participants will be asked to attend 11 study visits over a period of approximately 50 weeks and receive 3 doses of their assigned study vaccine: one at Entry, one at Week 8 and one at Week 20. Researchers will compare the results from participants who get the Trimer 4571 vaccine with results from participants who get the placebo vaccine. Participants, the researchers and the clinic staff will not know which vaccine participants are getting.

After Week 20, participants will be followed for 24 additional weeks with study visits and tests to monitor their health and safety and to see how the study vaccine affects the immune system and the virus.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Allocation: Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Randomized, double-blind, dose escalation
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Safety, Tolerability and Immunogenicity of Recombinant HIV Envelope Protein VRC-HIVRGP096-00-VP (Trimer 4571) Vaccine, in HIV-1 Infected Adults on Suppressive ART
• Actual Study Start Date: September 30, 2021
• Estimated Primary Completion Date: June 30, 2024
• Estimated Study Completion Date: January 31, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Randomized Blinded Trimer 4571 Vaccine 100mcg; Six (6) participants will receive Trimer 4571 vaccine 100mcg with 500mcg alum adjuvant as a 1ml intramuscular injection at Day 0, Week 8 and Week 20.	Biological: Trimer 4571 vaccine 100mcg with 500mcg alum adjuvant; Investigational vaccine composed of Trimer 4571 100mcg, alum (aluminum hydroxide suspension) adjuvant 500mcg, and phosphate buffered saline diluent; Other Names: HIV-1 Trimer 4571 Vaccine; VRC-HIVRGP096-00-VP
Placebo Comparator: Randomized Blinded Placebo for Trimer 4571 Vaccine 100mcg; Two (2) participants will receive the placebo control for Trimer 4571 vaccine 100mcg as a 1ml intramuscular injection at Day 0, Week 8 and Week 20.	Biological: Placebo control for Trimer 4571 vaccine 100mcg with 500mcg alum adjuvant; Volume matched control for Trimer 4571 vaccine 100mcg; Other Name: Phosphate buffered saline
Experimental: Randomized Blinded Trimer 4571 Vaccine 500mcg; Eighteen (18) participants will receive Trimer 4571 vaccine 500mcg with 500mcg alum adjuvant as a 1.1ml intramuscular injection at Day 0, Week 8 and Week 20.	Biological: Trimer 4571 vaccine 500mcg with 500mcg alum adjuvant; Investigational vaccine composed of Trimer 4571 500mcg, alum (aluminum hydroxide suspension) adjuvant 500mcg, and phosphate buffered saline diluent; Other Names: HIV-1 Trimer 4571 Vaccine; VRC-HIVRGP096-00-VP
Placebo Comparator: Randomized Blinded Placebo for Trimer 4571 Vaccine 500mcg; Six (6) participants will receive the placebo control for Trimer 4571 vaccine 500mcg as a 1.1ml intramuscular injection at Day 0, Week 8 and Week 20.	Biological: Placebo control for Trimer 4571 vaccine 500mcg with 500mcg alum adjuvant; Volume matched control for Trimer 4571 vaccine 500mcg; Other Name: Phosphate buffered saline

Outcome Measures

Primary Outcome Measures :

1. Safety and tolerability of three vaccinations of Trimer 4571 vaccine in adults with HIV on suppressive ART [ Time Frame: Day 0 through Week 44 ]
   The proportion of participants experiencing at least one Grade 3 or higher adverse event will be summarized within and across the Trimer 4571 vaccine 100mcg, Trimer 4571 vaccine 500mcg and placebo control vaccine groups. The number of adverse events in each group will also be summarized by severity, body system, and relationship to study vaccine using frequencies, percent, and 95% confidence intervals.

Secondary Outcome Measures :

1. Immunogenicity of three vaccinations of Trimer 4571 vaccine in adults with HIV on suppressive ART [ Time Frame: Baseline and Week 22 ]
   Comparison of the change in the serum ID50 neutralization titer of BG505.W6M.C2 virus between Trimer 4571 vaccine 100mcg, Trimer 4571 vaccine 500mcg, and placebo control vaccine. Vaccine responders will be as defined by either (i) 4-fold increase in neutralization titer from pre-vaccination to at least one virus in the curated virus panel at any protocol-specified time point post vaccination and/or (ii) Evidence of BG505.W2 neutralization at any protocol-specified time point post vaccination.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. HIV-1 infection, documented by any FDA-approved assay. NOTE: The term 'licensed' refers to a US FDA approved kit, which is required for all investigational new drug (IND) studies.
2. Receiving continuous antiretroviral therapy (ART) for at least 24 months (defined as no interruptions longer than 30 consecutive days) and with no changes in the components of the ART for at least 8 weeks prior to study entry. A change in formulation (for example tenofovir disaproxil fumarate to tenofovir alafenamide) will not be considered a change in ART.
3. Screening CD4+ cell count ≥200cells/mm3 obtained within 45 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent.

4. Plasma HIV-1 RNA levels < 50 copies/ml for at least 24 months on ART prior to study entry using a FDA-approved assay performed by any laboratory that has a CLIA certification or its equivalent. Participants must have at least one documented HIV-1 RNA < 50 copies/ml within 12 months prior to study entry. All available HIV-1 RNA measurements must be < 50 copies/ml during the 24 months prior to study entry except as allowed by the following note.

   NOTE: Unconfirmed plasma HIV-1 RNA > 50 copies/ml but <200 copies/mL is allowed if followed by a subsequent value < 50 copies/ml.

5. Screening HIV-1 RNA levels <50 copies/mL using a FDA-approved assay performed by any laboratory that has a CLIA certification or its equivalent within 45 days prior to entry.
6. Men and women ages > 18 years.

7. The following laboratory values obtained within 45 days prior to entry:

   • Hemoglobin ≥10 g/dL
   • Absolute neutrophil count (ANC) ≥1000/mm3
   • Platelet count ≥100,000/mm3
   • Creatinine ≤ 1.5x upper limit of normal (ULN)
   • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (SGPT) ≤2.5x ULN
8. Ability and willingness of participant to provide informed consent.
9. In the opinion of the investigator, no medical, mental health or other condition that precludes participation.
10. For persons who can become pregnant, negative serum or urine pregnancy test within 48 hours prior to entry by any US clinic or laboratory that has a CLIA certification or its equivalent, or is using a point-of-care (POC)/ CLIA-waived test. Persons who can become pregnant include women who have not been post-menopausal for at least 12 consecutive months, (i.e., who have had menses within the preceding 12 months) or women who have not undergone surgical sterilization (e.g. hysterectomy, bilateral oophorectomy, bilateral tubal ligation or salpingectomy). Self- report is acceptable documentation of menopause and sterilization.
11. All participants must agree not to participate in the conception process (eg, active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization), and if participating in sexual activity that could lead to pregnancy, the participant/partner must use at least one reliable form of contraception (condoms, with or without a spermicidal agent; a diaphragm or cervical cap with spermicide; an IUD; or hormone-based contraceptive), while receiving study treatment and for 12 weeks following the final study vaccine.

Exclusion Criteria:

1. Known to have been started on antiretroviral therapy within 3 months of the presumed or known date of first acquiring HIV-1 infection; i.e., treated during acute HIV-1 infection
2. Currently breastfeeding or pregnant
3. Known allergy/sensitivity or any hypersensitivity to components of study vaccine or their formulation.
4. Known chronic inflammatory conditions such as, but not limited to, rheumatoid arthritis, systemic lupus erythematosus, sarcoidosis, inflammatory bowel disease (i.e., Crohn's disease or ulcerative colitis), chronic pancreatitis, or autoimmune hepatitis, myositis, or myopathy.
5. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
6. Serious medical illness that requires systemic treatment and/or hospitalization within 30 days prior to entry.

7. Use of systemic immunomodulators (e.g., interleukins, interferons, Cyclosporine), systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry.

   NOTE: Participants receiving stable physiologic doses of glucocorticoids, defined as the equivalent of prednisone ≤10 mg/day, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving inhaled or topical corticosteroids, or topical imiquimod will not be excluded.

8. Participation in any HIV immunotherapy or therapeutic vaccination trials within 12 months prior to study entry.
9. History of positive HCV antibody with detectable HCV RNA in plasma within 48 Weeks prior to study entry. NOTE: Persons with positive HCV Ab but negative plasma HCV RNA are allowed to participate. Sites must document negative HCV RNA within 24 weeks of study entry.
10. Treatment for hepatitis C within 6 months prior to study entry.
11. History of positive HBsAg within 48 weeks prior to study entry.
12. History of severe reaction or anaphylaxis to prior vaccinations.
13. Body Mass Index >40kg/m2.
14. Receipt of Blood products or immune globulins within 16 weeks prior to Enrollment as per protocol section 5.3.2.
15. Receipt of Live attenuated vaccines within 4 weeks prior to enrollment.
16. Current allergen immunotherapy with antigen injections, unless on maintenance schedule.

Contacts and Locations

Contacts

Contact: Madhu Choudhary, MD; 412-383-1675; mac529@pitt.edu

Contact: Stacey Edick, PA-C; 412-383-1482; edicksm2@upmc.edu

Locations

United States, Ohio

AIDS Clinical Trials Unit/The Ohio State University; Not yet recruiting

Columbus, Ohio, United States, 43210

Contact: Lindsay M Summers, BS, MPH 614-293-8529 lindsay.summers@osumc.edu

Contact: Lucia J Niermann, BS 614-293-3550 lucia.niermann@osumc.edu

Principal Investigator: Susan L Koletar, MD

Sub-Investigator: Carlos D Malvestutto, MD, MPH

Sub-Investigator: William Maher, MD

United States, Pennsylvania

HIV/AIDS Clinical Research Unit / University of Pittsburgh; Recruiting

Pittsburgh, Pennsylvania, United States, 15213

Contact: Sherri Karas 412-383-1313 schesx@upmc.edu

Contact: Stacey Edick, PA-C 412-383-1482 edicksm2@upmc.edu

Sub-Investigator: Sharon Riddler, MD

Sub-Investigator: Deborah McMahon, MD

Sub-Investigator: Bernard Macatangay, MD

Principal Investigator: Madhu Choudhary, MD

Sub-Investigator: Ken Ho, MD

Sub-Investigator: Stacey Edick, PA-C

Sponsors and Collaborators

Madhu Chhanda Choudhary

National Institute of Allergy and Infectious Diseases (NIAID)

Investigators

• Principal Investigator: Madhu Choudhary, MD; University of Pittsburgh

More Information

• Responsible Party: Madhu Chhanda Choudhary, Associate Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04985760
• Other Study ID Numbers: DAIDS-ES 38763; U01AI152969 ( U.S. NIH Grant/Contract )
• First Posted: August 2, 2021
• Last Update Posted: April 12, 2022
• Last Verified: April 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Madhu Chhanda Choudhary, University of Pittsburgh:

HIV; Vaccine; Vaccination; Immune system; Antibody; Antibodies; broadly neutralizing; bnabs

Additional relevant MeSH terms:

HIV Infections; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Aluminum Hydroxide; Vaccines; Aluminum sulfate; Immunologic Factors; Physiological Effects of Drugs; Adjuvants, Immunologic; Antacids; Molecular Mechanisms of Pharmacological Action; Gastrointestinal Agents