HIV-1-infection
Conditions
Keywords
Antiretroviral therapy (ART), VRC07-523LS, 10E8.4/iMab, Monoclonal antibody, Bispecific antibody, Broadly neutralizing antibodies, Viral suppression, Ibalizumab, 10E8
Brief summary
This is an open-label phase 1b clinical trial enrolling people living with HIV (PLWH) who are antiretroviral therapy (ART)-naïve or have not been on ART for \> 24 weeks. This study will enroll PLWH to assess the safety, tolerability, and antiviral effect of bispecific and long-acting bNAbs, alone and in combination. The study will be conducted as a single center study at National Institute for Medical Research-Mbeya Medical Research Center (NIMR-MMRC) in Mbeya, Tanzania. 20 PLWH will be sequentially enrolled into one of 5 arms, each arm comprised of 4 participants. Sequential enrollment will occur in the following order: * Arm 1 will receive standard daily oral ART. * Arm 2 will receive a single dose of 10E8.4/iMab 600mg intravenous injection (IV). * Arm 3 will receive a single dose of 10E8.4/iMab 600mg intramuscular injection (IM). * Arm 4 will receive a single dose of 10E8.4/iMab 1800mg IV. * Arm 5 will receive a single dose of combination therapy with both 10E8.4/iMab 1800mg IV and VRC07-523LS 1200mg IV.
Detailed description
Although global initiatives have made great strides in controlling the human immunodeficiency virus (HIV) pandemic, HIV and acquired immune deficiency syndrome (AIDS) continue to impact the lives and livelihoods of a significant portion of the population. In 2019, 38 million individuals were living with HIV and 690,000 died of AIDS-related causes. Despite extensive global efforts for disease control over the last 20 years, 1.7 million individuals contract HIV annually. Antiretroviral therapy (ART) reduces morbidity and mortality associated with HIV by suppressing viral replication but does not eradicate infection. There are barriers to universal ART use that include toxicities, costs, drug resistance, and the need for lifelong adherence. To overcome these barriers, HIV broadly neutralizing antibodies (bNAbs) represent a novel approach to HIV prevention and treatment. The primary endpoint of change in viral load will be assessed at day 14. Participants will then transition to Step 2, during which all participants will take standard daily oral ART and have viral load monitored through Step 2 week 48.
Interventions
DRUGART
ART is a combination of three or more drugs from different classes of antiretroviral medication.
DRUG10E8.4/iMab
10E8.4/iMab is an engineered bispecific antibody with two arms combined into a single molecule that exhibits synergistic enhancement of antiviral activity. 10E8.4/iMab will be administered IV at the 600mg or 1800mg dose or IM at 600mg dose to participants in Step 1 per the Schedule of Events (SOE) based on the arm the participant is assigned.
DRUGVRC07-523LS
VRC07-523LS is an engineered variant of VRC01, a bNAb that targets the CD4 binding site of the HIV-1 envelope. VRC07-523LS will be administered IV at the 1200mg dose to participants in Step 1 per the SOE.
Sponsors
Henry M. Jackson Foundation for the Advancement of Military Medicine
US Military HIV Research Program
National Institute of Allergy and infectious Diseases (NIAID)/Vaccine Research Center (VRC)
David Ho
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Participants are assigned to 1 to 5 arm sequentially.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
1. Able to read and write in Kiswahili and/or English 2. Able and willing to provide written informed consent 3. Passes Test of Understanding (TOU) 4. Aged 18-50 years, inclusive 5. Antiretroviral Therapy (ART)-naïve or no ART for \> 24 weeks at the time of screening 6. HIV RNA 1,000-100,000 copies/mL 7. CD4 ≥ 500 cells/mm3 8. Laboratory criteria at screening within protocol-specified limits for blood, chemistry and urinalysis 9. Willing and able to participate in study visits and procedures for up to 50 weeks 10. Willing and able to begin ART as directed during the study 11. Willing and able to use barrier protection during sex with partners without HIV or partners with unknown HIV status throughout Step 1 and until viral suppression \<200 copies/mL is confirmed in Step 2 12. Willing and able to adhere to the following contraception requirements: 1. Participants who are able to become pregnant must agree to use at least one method of highly effective contraception if participating in sexual activity that could lead to pregnancy. This must begin at least 14 days prior to study enrollment. 2. Participants who engage in sexual activity that could lead to their partner becoming pregnant and who are of reproductive potential must agree to use a barrier method of contraception to avoid pregnancy in a sexual partner of reproductive potential. The barrier method must be used for the duration of the study.
Exclusion criteria
1. Weight \>100 kg 2. Previous receipt of humanized or human monoclonal antibody whether licensed or investigational (other than for the prevention and/or treatment of SARS-CoV2/COVID-19) 3. History of viral failure on two or more ART regimens 4. Planned or anticipated need for enfuvirtide, maraviroc, fostemsavir, or ibalizumab for antiretroviral therapy. 5. AIDS-defining illness, as enumerated by the WHO Stage 3 or 4, within the six months prior to enrollment 6. Ongoing oral thrush 7. Active injection or other recreational drug use within the previous 12 months that, in the opinion of the investigator, would impede the participant's ability to safely and consistently adhere to the study protocol 8. History of a severe allergic reaction with generalized urticaria, angioedema or anaphylaxis in the 2 years prior to enrollment. 9. History of chronic urticaria requiring daily treatment 10. Known active hepatitis B virus infection or positive hepatitis B surface antigen at any time in the past 11. Known active hepatitis C virus infection or positive hepatitis C antibody at any time in the past 12. Untreated syphilis 13. Estimated GFR \< 50 mL/min within the past 90 days 14. Pregnant or breast-feeding 15. Receipt of licensed vaccine or other investigational study agent within 28 days prior to enrollment or any past participation in an investigational HIV vaccine study with receipt of active product 16. Current or planned participation in another interventional clinical trial during the study period, including clinical trials of investigational new drugs or investigating a new application for an approved medication 17. Chronic or recurrent use of medications that modify host immune response, such as oral steroids, parenteral steroids, or cancer chemotherapy (note: locally-acting medications-such as inhaled, topical, or intra-articular steroids-are allowed) 18. Any other chronic or clinically significant medical condition that in the opinion of the investigator would jeopardize the safety or rights of the participant including, but not limited to: diabetes mellitus type I, chronic hepatitis, renal failure; OR clinically significant forms of: drug or alcohol abuse, mental illness, severe asthma, autoimmune disease, decompensated psychiatric disorders, hypertension, heart disease, or cancer 19. Any medications that, in the opinion of the investigator, would preclude intramuscular injections 20. Study site employee
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Grade 3 or higher antibody-related reactogenicity and adverse events | Up to Week 48 in Step 2 | Includes potentially life-threatening, or fatal events. |
| Change in plasma HIV RNA from day 0 to day 14 | Day 0 and Day 14 in Step 1 | Viral RNA copies/mL will be measured. |
| Proportion of participants with HIV RNA < 50 copies/mL at day 14 | Up to Day 14 in Step 1 | Percentage of participants will be calculated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Peripheral HIV RNA | Up to Week 48 in Step 2 | Serum level of viral RNA (copies/mL) will be measured. |
| Plasma level of 10E8.4/iMab | Up to Week 48 in Step 2 | Serum level of 10E8.4/iMab (ug/mL) will be measured. |
| Plasma level of VRC07-523LS | Up to Week 48 in Step 2 | Serum level of VRC07-523LS (ug/mL) will be measured. |
| CD4 receptor occupancy | Up to Week 48 in Step 2 | The percentage of CD4 cells that bind to 10E8.4/iMab will be measured. |
| Proportions of participants with HIV RNA <50 copies/mL | Up to Week 48 in Step 2 | Percentage of participants will be calculated. |
| Neutralization sensitivity of 10E8.4/iMab | Up to Week 48 in Step 2 | Half-maximal inhibitory concentration (IC50) will be measured. |
| Neutralization sensitivity of VRC07-523LS | Up to Week 48 in Step 2 | Half-maximal inhibitory concentration (IC50) will be measured. |
| Presence of anti-bNAb antibodies | Up to Week 48 in Step 2 | The anti-drug antibody titer in serum will be measured. |
| HIV reservoir size | Up to Week 48 in Step 2 | Will measure HIV DNA in copies/million cells. |
| Proportions of participants with HIV RNA < 200 copies/mL | Up to Week 48 in Step 2 | Percentage of participants will be calculated. |
| Proportions of participants with HIV RNA <1000 copies/mL | Up to Week 48 in Step 2 | Percentage of participants will be calculated. |
Countries
Tanzania
Outcome results
None listed