10E8.4/iMab Bispecific Antibody in HIV-uninfected and HIV-infected Adults
- Conditions
- HIV-1-infection
- Interventions
- Biological: 10E8.4/iMab
- Registration Number
- NCT03875209
- Lead Sponsor
- David Ho
- Brief Summary
Many HIV-infected individuals mount a broad neutralizing serologic response 2-3 years after infection. Broadly neutralizing antibodies might play an important role in protection from acquisition of HIV infection because they can protect macaques from infection, and the presence of anti-HIV antibodies was the only positive correlate of protection in an HIV vaccine efficacy trial (RV144 trial). HIV neutralizing antibodies also have the potential to alter the course of HIV infection in humans. Therefore, these antibodies might be useful to both prevent and treat HIV-1 infection.
This is a phase 1 dose escalating clinical trial to evaluate the safety, tolerability, pharmacokinetics and the antiretroviral effects of a novel bispecific monoclonal antibody 10E8.4/iMab in HIV-infected and HIV-uninfected individuals. The study will be conducted as a multi-center study at the Columbia University Medical Center in New York City and the Orlando Immunology Center in Orlando, Florida.
- Detailed Description
There are 4 study Arms as it is possible that pharmacokinetics (PK) may differ between HIV-1-uninfected individuals (Arms 1, 2 and 4) and HIV-1-infected and viremic individuals (Arm 3). Safety and tolerability as well as PK may differ between the IV and SC routes, Arms 1, 2 and 4.
A dose escalation design has been used to establish safety and tolerability at very low doses of 10E8.4/iMab as this is a first in man study. Once demonstrated, dose levels would be increased to dosing levels thought to be more clinically relevant.
The numbers of subjects receiving active antibody in each study arm are relatively balanced such that an initial evaluation of the primary endpoint with additional dosing to provide insights into both PK and antiviral activity as well as some exploratory endpoints such as immunogenicity will be possible.
This study is a phase 1 clinical trial to evaluate the safety and tolerability, pharmacokinetics and the antiretroviral activity of the bispecific monoclonal antibody 10E8.4/iMab in HIV-infected and HIV-uninfected individuals.
HIV uninfected, healthy volunteers will be administered either one intravenous infusion of 10E8.4/iMab at one of five increasing dose levels (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 10 mg/kg and 30 mg/kg) or one SC injection of 1 mg/kg, 2.5 mg/kg or 10 mg/kg or placebo and will be followed for 24 weeks after 10E8.4/iMab administration. HIV-infected volunteers will be administered one intravenous infusion of 10E8.4/iMab at one of three increasing dose levels (3 mg/kg, 10 mg/kg and 30 mg/kg).
Arm 1 consists of 3 groups: Group A: 0.3 mg/kg IV, N=3; Group B: 1mg/kg SC, N=3; and Group C: 1mg/kg IV, N=3. All HIV-1 uninfected, dosed once.
Arm 2 consists of 3 groups: Group D: 3mg/kg, N=6; Group E: 10mg/kg, N=6; and Group F: 30 mg/kg, N=6. All HIV-1 uninfected, dosed IV once.
Arm 3 consists of 2 groups: H: 10mg/kg, N=4 and Group I: 30 mg/kg, N=4. All HIV-1 infected, dosed IV once.
Arm 4 consists of 2 groups: Group J: 2.5 mg/kg, N=9, 6 active, 3 placebo; Group K: 10mg/kg, N=9, 6 active, 3 placebo, dosed SC once.
Since the safety and tolerability profiles, as well as the PK profile might differ between HIV-infected and HIV-uninfected individuals, dose-escalation is planned in both study populations. Dosing in Arm 1 Groups A, B and C; Arm 2 Groups D and E; and Arm 4 Groups J and K will be done prior to initiation of dosing in Arm 3 due to safety considerations.
Arm 3 will include HIV-infected individuals off antiretroviral therapy (ART) for at least 4 weeks with plasma HIV-1 RNA levels \< 100,000 copies/ml (both ART naïve and individuals that discontinued ART due to intolerance or by choice can be included in this group), or HIV-infected individuals on stable ART with plasma HIV-1 RNA levels \> 1000 copies/ml.
The stated numbers of participants are the minimal number per dosing group. A safety monitoring committee may request additional enrollment in a specific Arm or Group based on the occurrence of dose limiting toxicities defined as any Grade 3 or greater adverse event that is probably or definitely related to the investigational product.
Study visits are all outpatient and include:
1. a screening phase of up to 2 visits
2. an administration visit at which 10E8.4/iMab is given either IV or SC in doses based on body weight and specific Arm and Group assignment.
3. follow up visits that will occur at days 2, 7, 10 and weeks 2, 3, 4, 6, 8, 12 and 24. Subjects who received placebo SC may not be required to return for the week 24 visit.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 54
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Arm 1: 10E8.4/iMab IV or SC HIV- 10E8.4/iMab Arm 1; Groups A-C; 3 dosing groups: HIV-uninfected individuals Arm 2: 10E8.4/iMab IV HIV- 10E8.4/iMab Arm 2; Groups D-F; 3 dosing groups: HIV-uninfected individuals Arm 3 and 3a: 10E8.4/iMab IV HIV+ 10E8.4/iMab Arm 3; Group H; 1 dosing group: HIV-infected individuals with HIV-1 RNA levels between 1,000 and 100,000 copies/mL and cluster of differentiation 4 (CD4)\>350 cells/mm3; Arm 3a; Group I; 1 dosing group: HIV-infected and suppressed individuals Arm 4: 10E8.4/iMab SC HIV- 10E8.4/iMab Arm 4; Groups J and K: HIV-uninfected individuals
- Primary Outcome Measures
Name Time Method Safety of the highest single intravenous dose of 10E8.4/iMab in HIV uninfected individuals. Safety of a single dose of intravenous dose of 10E8.4/iMab in HIV uninfected individuals 24 weeks Percentage of subjects experiencing a dose limiting toxicity defined as a Grade 3 or 4 adverse events as per the toxicity grading scale for healthy volunteers enrolled in preventative vaccine trials
Safety of the highest single intravenous dose of 10E8.4/iMab in HIV infected individuals Safety of a single dose of intravenous dose of 10E8.4/iMab in HIV uninfected individuals 24 weeks Percentage of subjects experiencing a dose limiting toxicity defined as a Grade 3 or more adverse event as per the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events v 2.1
Injection site reactions associated with a single subcutaneous injection of 10 E8.4/iMab in HIV uninfected individuals 24 weeks Percentage of injections associated with a Grade 2 or greater injection site reaction as per the toxicity grading scale for healthy volunteers enrolled in preventative vaccine trials
Systemic infusion reaction associated with the intravenous administration of any dose of 10E8.4/iMab 24 weeks Percentage of subjects receiving intravenous 10E8.4/iMab as per CTCAE version 5.0.
- Secondary Outcome Measures
Name Time Method Serum levels 10E8.4/iMab after the highest single dose of 10E8.4/iMab given intravenously to HIV infected and uninfected individuals 7 days levels of 10E8.4/iMab expressed in ng/mL serum
Antiviral activity of the highest single dose of 10E8.4/iMab given intravenously to viremic HIV infected individuals 28 days changes in log HIV-1 RNA levels from baseline
Serum levels of 10E8.4/iMab after the highest single dose of 10E8.4/iMab given intravenously to HIV infected and uninfected individuals 14 days levels of 10E8.4/iMab expressed in ng/mL serum
Serum levels of 10E8.4/iMab after the highest single dose of 10E8..4/iMab given subcutaneously to HIV uninfected individuals 56 days levels of 10E8.4/iMab expressed in ng/mL serum
Serum levels of 10E8.4/iMab after the highest single dose of 10E8.4/iMab given intravenously to HIV infected and uninfected individuals. 56 days levels of 10E8.4/iMab expressed in ng/mL serum
Percentage of subjects developing antibodies to 10E8.4/iMab after any single intravenous or subcutaneous dose of 10E8.4/iMab 84 days Percent of study participants
Trial Locations
- Locations (2)
Orlando Immunology Center
🇺🇸Orlando, Florida, United States
Columbia University Research Unit
🇺🇸New York, New York, United States