Clinical trial NCT03739996: Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) for Viral Suppression in Adults Living With HIV-1
Official title: A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) to Maintain Viral Suppression in Adults Living With HIV-1
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: ViiV Healthcare
First posted: 2018-11-14
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

Eligibility criteria: Step 1 Inclusion Criteria:

* 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 Exclusion Criteria:

* 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

Primary outcomes:
measure: 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)
timeFrame: 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).
measure: Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 44
timeFrame: Measured from Step 2 entry through Step 2 Week 44
Secondary outcomes:
measure: Median Concentrations of VRC07-523LS
timeFrame: Measured at Step 2 Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48
measure: Median Concentration of CAB LA
timeFrame: Measured at Step 2 Week 4, 8, 24, and 48
measure: ARV Resistance of Breakthrough Isolates
timeFrame: Measured from Step 2 entry through Step 2 Week 48
measure: Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 24
timeFrame: Measured from Step 2 entry through Step 2 Week 24
measure: Cumulative Probability of Confirmed Virologic Failure or Premature Treatment Discontinuation at or Prior to Step 2 Week 44
timeFrame: Measured from Step 2 entry through Step 2 Week 44
measure: Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL at or Prior to Step 2 Week 44
timeFrame: Measured from Step 2 entry through Step 2 Week 44
measure: Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL at or Prior to Step 2 Week 24
timeFrame: Measured from Step 2 entry through Step 2 Week 24
measure: Cumulative Probability of Confirmed HIV-1 RNA ≥ 50 Copies/mL or Premature Treatment Discontinuation at or Prior to Step 2 Week 44
timeFrame: Measured from Step 2 entry through Step 2 Week 44
measure: Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Step 2 Week 44
timeFrame: Step 2 Week 44
measure: Frequency of Anti-Drug Antibodies (ADA) Against VRC07-523LS
timeFrame: Measured at Step 2 Week 28 and 48
measure: 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.
timeFrame: Measured from Step 1 entry through the end of Step 1 (for a maximum of 5 weeks)
measure: Proportion of Participants Who Prematurely Discontinued Oral CAB or the CAB LA Plus VRC07-523LS Combination
timeFrame: Measured from Step 1 entry through the end of Step 2 (for a maximum of 53 weeks)
measure: 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.
timeFrame: Measured from Step 1 entry through entire study follow-up (for a maximum of 101 weeks)
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama CRS
state: Alabama
city: San Diego
country: United States
facility: UCSD Antiviral Research Center CRS
state: California
city: San Francisco
country: United States
facility: Ucsf Hiv/Aids Crs
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Baltimore
country: United States
facility: Johns Hopkins University CRS
state: Maryland
city: Saint Louis
country: United States
facility: Washington University Therapeutics (WT) CRS
state: Missouri
city: Newark
country: United States
facility: New Jersey Medical School Clinical Research Center CRS
state: New Jersey
city: New York
country: United States
facility: Weill Cornell Chelsea CRS
state: New York
city: New York
country: United States
facility: Columbia P&S CRS
state: New York
city: New York
country: United States
facility: Weill Cornell Uptown CRS
state: New York
city: Rochester
country: United States
facility: University of Rochester Adult HIV Therapeutic Strategies Network CRS
state: New York
city: Chapel Hill
country: United States
facility: Chapel Hill CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Cincinnati Clinical Research Site
state: Ohio
city: Columbus
country: United States
facility: Ohio State University CRS
state: Ohio
city: Philadelphia
country: United States
facility: Penn Therapeutics, CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico AIDS Clinical Trials Unit CRS
Study officials:
affiliation: Northwestern University CRS
name: Babafemi Taiwo, MBBS
role: STUDY_CHAIR
affiliation: Hospital of the University of Pennsylvania CRS
name: Pablo Tebas, MD
role: STUDY_CHAIR
affiliation: Weill Cornell Chelsea CRS
name: Leah Burke, MD
role: STUDY_CHAIR
References: