Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) for Viral Suppression in Adults Living With HIV-1
- Conditions
- HIV Infections
- Interventions
- Drug: Nucleoside Reverse Transcriptase Inhibitors (NRTIs)Drug: Standard of Care (SOC) ART
- Registration Number
- NCT03739996
- Brief Summary
The purpose of this study was to assess the safety, tolerability, antiviral activity, and pharmacokinetics of long-acting cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody VRC-HIVMAB075-00-AB (VRC07-523LS), in adults living with HIV-1 with suppressed plasma viremia.
- Detailed Description
This study had a single, open-label arm and was conducted in three steps.
At Step 1 entry, all participants discontinued their current antiretroviral therapy (ART) regimen, except for the 2 nucleoside reverse transcriptase inhibitors (NRTIs) and started oral CAB. Viral load monitoring occurred at entry, Week 4, and, conditionally, Week 5.
During Step 1, participants who tolerated oral CAB plus their two NRTIs, maintained viral suppression, and met the other Step 2 eligibility requirements, registered for Step 2. Participants in Step 1 who were not eligible for Step 2 returned to their standard of care (SOC) regimen and were followed for an additional 4 weeks before being taken off the study.
In Step 2, participants received CAB LA every 4 weeks through Step 2 Week 44 (12 injections) plus VRC07-523LS every 8 weeks through Step 2 Week 40 (6 infusions). Viral load monitoring occurred every 2 weeks through Week 8 and then every 4 weeks through Week 48. Any participant with a viral load of HIV-1 RNA ≥ 200 copies/mL had to attend an additional virologic failure confirmation visit within 14 days of the measured value. If virologic failure was confirmed (i.e., two consecutive HIV-1 RNA values ≥ 200 copies/mL), the participant transitioned to Step 3.
After completion of Step 2 (Week 48), confirmed virologic failure, or premature treatment discontinuation, all participants who received any CAB LA or VRC07-523LS entered Step 3 and returned to SOC ART for 48 weeks, with visits at step entry and weeks 4, 12, 24, 36, and 48.
The study's primary virology outcome pertains to Step 2 and only includes participants who started the CAB LA plus VRC07-523LS combination. The study's primary safety outcome pertains to Step 2 and Step 3 follow-up for participants who started the CAB LA plus VRC07-523LS combination.
Study visits included physical examinations, clinical assessments, and blood and urine collection.
The study opened to accrual in late December 2019. However, in March 2020 the study temporarily closed to screening and enrollment (including registration to Step 2) due to the COVID-19 pandemic. No participant had reached Step 2 of the study when the pause occurred. Participants in Step 1 were instructed to immediately stop the oral CAB plus 2 NRTI combination, resume their SOC regimen, and discontinue the study. The study reopened to screening and enrollment in September 2020. Analyses for this study only included participants who enrolled after the study reopened in September 2020. Participants previously enrolled were invited to rescreen and reenroll, if still eligible.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 75
-
Individual with HIV-1
-
On a three-drug ART regimen for at least 8 weeks that includes a boosted protease inhibitor (PI), a nonnuceloside reverse transcriptase inhibitor (NNRTI), or an integrase inhibitor (INSTI) plus two nuclesodie reverse transcriptase inhibitors (NRTI) with no history of switch due to virologic failure.
-
CD4+ cell count greater than or equal to 350 cells/mm^3
-
Virally suppressed (< 50 copies/mL) within 2 years prior to study entry
-
Susceptibility to VRC07-523LS based on IC50 less than or equal to 0.25 ug/mL and a Maximum Percent Inhibition > 98% using the Monogram PhenoSense Assay
-
Certain laboratory values obtained within 60 days prior to study entry and in an acceptable range
-
For participants of child-bearing potential:
- A negative serum or urine pregnancy test within 48 hours prior to study entry
- If participating in sexual activity that could lead to pregnancy, must agree to use an effective form of contraception.
-
Negative HBsAg result
-
Negative hepatitis C virus antibody
-
Ability and willingness to provide written informed consent
Step 1
- Any previous receipt of humanized or human monoclonal antibody (licensed or investigational).
- Weight greater than 115 kg or less than 53 kg.
- AIDS-defining illness within 60 days prior to study entry.
- History of a severe allergic reaction within 2 years prior to study entry.
- Currently breastfeeding or pregnant.
- Active drug or alcohol use or dependence that would interfere with adherence to study requirements.
- Acute or serious illness that requires systemic treatment, quarantine, and/or hospitalization within 30 days prior to entry.
- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry.
- Treatment for hepatitis C within 24 weeks prior to study entry.
- Vaccinations within 7 days prior to study entry.
- Initiation of ART during acute HIV-1 infection (as determined by the site investigator by history and/or available medical records).
- Personal or known family history of prolonged QT syndrome or a clinically significant finding on the screening electrocardiogram (ECG) based on an assessment of the screening ECG by that site investigator.
- Unstable liver disease or known biliary abnormalities
- Moderate or severe hepatic impairment (Class B or C) as determined by Child-Pugh classification.
- History of seizures or treatment for seizures within the past 2 years prior to study entry.
- Current acute illness that in the opinion of the investigator will prevent the participant from complying with study visits.
Step 2 Inclusion Criteria:
-
HIV-1 RNA less than 50 copies/mL at week 4 (Step 1), or HIV-1 RNA of 50-199 copies/mL at week 4 followed by HIV-1 RNA less than 50 copies/mL at week 5 (Step 1).
-
For participants of child-bearing potential:
- A negative serum or urine pregnancy test within 48 hours prior to step 2 entry
- If participating in sexual activity that could lead to pregnancy, continued agreement to use an effective form of contraception.
Step 2 Exclusion Criteria:
- Discontinuation or temporary hold of oral CAB or NRTIs for greater than 7 consecutive days for any reason during Step 1.
- Grade 3 or 4 adverse event thought to be related to oral CAB during Step 1 according to the site investigator.
- Vaccination (e.g., influenza) within 7 days prior to the Step 2 registration.
- Currently breastfeeding or pregnant.
- Any greater than or equal to Grade 2 ALT (greater than 2.5 times ULN) that developed during Step 1.
Step 3 Inclusion Criterion:
- Received any CAB LA or VRC07-523LS during Step 2.
Step 3 Exclusion Criterion:
- None
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description CAB LA + VRC07-523LS Long-Acting Injectable Cabotegravir (CAB LA) Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections). VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions). Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks. CAB LA + VRC07-523LS VRC07-523LS Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections). VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions). Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks. CAB LA + VRC07-523LS Standard of Care (SOC) ART Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections). VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions). Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks. CAB LA + VRC07-523LS Oral Cabotegravir (CAB) Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections). VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions). Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks. CAB LA + VRC07-523LS Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Step 1: CAB administered orally as one 30 mg tablet once daily, plus two NRTIs, for up to 5 weeks. Step 2: CAB LA loading dose (600 mg) administered as one IM injection at Step 2 entry study visit, and maintenance dose (400 mg), starting at 4 weeks after CAB LA loading dose, and then every 4 weeks through Week R2+44 (for a total of 12 injections). VRC07-523LS (40 mg/kg) administered as an IV infusion starting at Step 2 entry and then every 8 weeks through Week R2+40 (for a total of 6 infusions). Step 3: Standard of Care (SOC) ART regimen for approximately 48 weeks.
- Primary Outcome Measures
Name Time Method Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) or Premature Discontinuation Due to an AE (Regardless of Grade) That is Related To Step 2 Study Treatment (CAB LA Plus VRC07-523LS) Measured from Step 2 entry through the remaining study follow-up (e.g., any time on Step 2 or Step 3 for a maximum follow-up time of 96 weeks). The proportion of participants reporting a grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) adverse event OR premature discontinuation due to an adverse event (regardless of grade) that the clinical management committee judged to be at least possibly related to the CAB LA plus VRC07-523LS combination.
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 44 Measured from Step 2 entry through Step 2 Week 44 Virologic failure is defined as confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 200 copies/mL at or prior to Step 2 Week 44 of the CAB LA plus VRC07-523LS combination.
- Secondary Outcome Measures
Name Time Method Median Concentration of CAB LA Measured at Step 2 Week 4, 8, 24, and 48 Concentrations of long-acting cabotegravir, measured in plasma, at select time points in Step 2
Median Concentrations of VRC07-523LS Measured at Step 2 Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48 Concentrations of VRC07-523LS, measured in serum, at selected time points in Step 2.
ARV Resistance of Breakthrough Isolates Measured from Step 2 entry through Step 2 Week 48 ARV resistance testing was conducted on samples obtained when confirmed virologic failure (two consecutive HIV-1 RNA values ≥ 200 copies/mL) occurred. Interpretation of resistance results, pertaining to integrase inhibitor resistance mutations, was obtained using the Stanford HIVDB Algorithm Version 9.3 (released 2022-11-20).
Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 24 Measured from Step 2 entry through Step 2 Week 24 Virologic failure defined as confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 200 copies/mL
Cumulative Probability of Confirmed Virologic Failure or Premature Treatment Discontinuation at or Prior to Step 2 Week 44 Measured from Step 2 entry through Step 2 Week 44 Virologic failure, defined as confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 200 copies/mL or premature treatment discontinuation, defined as the date at which a participant ended Step 2 treatment (CAB LA and VRC07-523LS), for any reason, without receiving all 12 CAB LA injections and 6 VRC07-523LS infusions, at or prior to Step 2 Week 44.
Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL at or Prior to Step 2 Week 44 Measured from Step 2 entry through Step 2 Week 44 Confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 50 copies/mL measured at or prior to Step 2 Week 44.
Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL at or Prior to Step 2 Week 24 Measured from Step 2 entry through Step 2 Week 24 Confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 50 copies/mL measured at or prior to Step 2 Week 24.
Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL or Premature Treatment Discontinuation at or Prior to Step 2 Week 44 Measured from Step 2 entry through Step 2 Week 44 Confirmed (i.e., two consecutive values) HIV-1 RNA ≥ 50 copies/mL or premature treatment discontinuation, defined as the date at which a participant ended Step 2 treatment (CAB LA and VRC07-523LS), for any reason, without receiving all 12 CAB LA injections and 6 VRC07-523LS infusions, at or prior to Step 2 Week 44.
Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Step 2 Week 44 Step 2 Week 44 The proportion of participants with HIV-1 RNA ≥ 50 copies/mL, HIV-1 RNA \< 50 copies/mL, and without data in Step 2 Week 44 window (days 295-322 from Step 2 entry) as defined by the FDA Snapshot algorithm.
Frequency of Anti-Drug Antibodies (ADA) Against VRC07-523LS Measured at Step 2 Week 28 and 48 Number of participants who were anti-drug antibody (ADA) negative or ADA positive calculated at each sampled timepoint.
Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) or Premature Discontinued Due to an AE (Regardless of Grade) That is Related to Oral CAB. Measured from Step 1 entry through the end of Step 1 (for a maximum of 5 weeks) The proportion of participants reporting a grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) adverse event OR premature discontinuation due to an adverse event (regardless of grade) that the clinical management committee judged to be at least possibly related to oral CAB.
Based on the Division of AIDS Table for Grading the Severity of Adult and Pedatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017.Proportion of Participants Who Prematurely Discontinued Oral CAB or the CAB LA Plus VRC07-523LS Combination Measured from Step 1 entry through the end of Step 2 (for a maximum of 53 weeks) The proportion of participants who discontinued, for any reason, oral CAB (during Step 1) or the CAB LA plus VRC07-523LS combination.
Proportion of Participants Experiencing a Grade 3 or Higher Adverse Event (AE) That is Related to Oral CAB or the CAB LA Plus VRC07-523LS Combination. Measured from Step 1 entry through entire study follow-up (for a maximum of 101 weeks) The proportion of participants reporting a grade 3 (severe), grade 4 (potentially life-threatening), or grade 5 (death) that the clinical management committee judged to be at least possibly related to oral CAB or the CAB LA plus VRC07-523LS combination.
Based on the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events (DAIDS AE Grading Table), corrected Version 2.1, July 2017.
Trial Locations
- Locations (18)
Alabama CRS
🇺🇸Birmingham, Alabama, United States
UCSD Antiviral Research Center CRS
🇺🇸San Diego, California, United States
Ucsf Hiv/Aids Crs
🇺🇸San Francisco, California, United States
University of Colorado Hospital CRS
🇺🇸Aurora, Colorado, United States
Northwestern University CRS
🇺🇸Chicago, Illinois, United States
Johns Hopkins University CRS
🇺🇸Baltimore, Maryland, United States
Washington University Therapeutics (WT) CRS
🇺🇸Saint Louis, Missouri, United States
New Jersey Medical School Clinical Research Center CRS
🇺🇸Newark, New Jersey, United States
Weill Cornell Chelsea CRS
🇺🇸New York, New York, United States
Columbia P&S CRS
🇺🇸New York, New York, United States
Weill Cornell Uptown CRS
🇺🇸New York, New York, United States
University of Rochester Adult HIV Therapeutic Strategies Network CRS
🇺🇸Rochester, New York, United States
Chapel Hill CRS
🇺🇸Chapel Hill, North Carolina, United States
Cincinnati Clinical Research Site
🇺🇸Cincinnati, Ohio, United States
Ohio State University CRS
🇺🇸Columbus, Ohio, United States
Penn Therapeutics, CRS
🇺🇸Philadelphia, Pennsylvania, United States
University of Washington AIDS CRS
🇺🇸Seattle, Washington, United States
Puerto Rico AIDS Clinical Trials Unit CRS
🇵🇷San Juan, Puerto Rico