A Study of Long-Acting Cabotegravir Plus VRC-HIVMAB075-00-AB (VRC07-523LS) to Maintain Viral Suppression in Adults Living With HIV-1
试验速览
- 阶段
- 2 期
- 状态
- 已完成
- 入组人数
- 75
- 试验地点
- 18
- 主要终点
- 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)
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
- •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
- •Step 3 Inclusion Criterion:
- •Received any CAB LA or VRC07-523LS during Step
- •Step 3 Exclusion Criterion:
研究组 & 干预措施
CAB LA + 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.
干预措施: Oral Cabotegravir (CAB) (Drug)
CAB LA + 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.
干预措施: Nucleoside Reverse Transcriptase Inhibitors (NRTIs) (Drug)
CAB LA + 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.
干预措施: Long-Acting Injectable Cabotegravir (CAB LA) (Drug)
CAB LA + 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.
干预措施: VRC07-523LS (Biological)
CAB LA + 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.
干预措施: Standard of Care (SOC) ART (Drug)
结局指标
主要结局
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)
时间窗: 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 2017
Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 44
时间窗: 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.
次要结局
- Median Concentration of CAB LA(Measured at Step 2 Week 4, 8, 24, and 48)
- Median Concentrations of VRC07-523LS(Measured at Step 2 Week 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48)
- ARV Resistance of Breakthrough Isolates(Measured from Step 2 entry through Step 2 Week 48)
- Cumulative Probability of Confirmed Virologic Failure at or Prior to Step 2 Week 24(Measured from Step 2 entry through Step 2 Week 24)
- 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)
- 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)
- 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)
- 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)
- Proportion of Participants With HIV-1 RNA ≥ 50 Copies/mL at Step 2 Week 44(Step 2 Week 44)
- Frequency of Anti-Drug Antibodies (ADA) Against VRC07-523LS(Measured at Step 2 Week 28 and 48)
- 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))
- 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))
- 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))