HIV Infections
Conditions
Keywords
Human Monoclonal Antibody
Brief summary
The study will evaluate the safety and therapeutic efficacy of the human monoclonal antibody (mAb) VRC-HIVMAB060-00-AB (VRC01), when administered during analytic treatment interruption (ATI), in adults who began antiretroviral therapy (ART) during early acute HIV infection.
Detailed description
Human monoclonal antibodies (mAbs) may have the potential to treat HIV infection by preventing the spread of the virus. This study will evaluate an experimental mAb known as VRC-HIVMAB060-00-AB (VRC01). The purpose of this study is to evaluate the safety and therapeutic efficacy of VRC01, when administered during analytic treatment interruption (ATI), in adults who began antiretroviral therapy (ART) during early acute HIV infection. The study will enroll participants from the RV 254 study who were diagnosed during early acute HIV infection and who have been on ART. At study entry, participants will stop taking their antiretroviral (ARV) medications. They will be randomly assigned to receive an intravenous (IV) infusion of VRC01 or placebo at Weeks 0 (study entry), 3, 6, 9, 12, 15, 18, 21, and 24. For 7 days following each infusion, participants will be asked to record and report any symptoms to study researchers. In addition to the infusion visits, participants will attend follow-up visits for 48 weeks. Study visits may include physical examinations, blood collection, and urine collection. Neurocognitive testing will take place at select study visits. Some participants may take part in optional study procedures including mucosal secretion collection, MRI brain scan, colon biopsy, lymph node biopsy, leukapheresis, and lumbar puncture. Study staff will monitor participants' HIV throughout the study, and participants will end their participation in the study and restart their ARV medications, if needed.
Interventions
BIOLOGICALVRC01
40 mg/kg; administered IV
BIOLOGICALPlacebo for VRC01
Sodium Chloride for Injection 0.9%, USP; administered IV
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
20 Years to 50 Years
Healthy volunteers
No
Inclusion criteria
* Able and willing to provide written informed consent or, in the case of illiteracy, witnessed verbal informed consent with documentation of a thumbprint in lieu of a signature. * Passes Test of Understanding. * Man or woman aged 20-50 years. * Initiated on ART during acute HIV infection (Fiebig Stage I to III at RV 254 enrollment). * Prescribed ART for at least 24 months prior to enrollment. * HIV-1 RNA less than 50 copies/mL on at least three consecutive measurements within the past 12 months. * Integrated HIV DNA in peripheral blood mononuclear cells (PBMCs) below the level of detection (1 copy/10\^5 PBMCs) within 6 months prior to enrollment. * Last documented peripheral blood CD4 greater than 400 cells/mm\^3 within 3 months prior to enrollment. * No HIV-related or AIDS-defining illness within 6 months prior to enrollment. * In general good health. * Able to participate in study visits. Female-Specific Criteria: * Agrees not to become pregnant from the time of study enrollment until the last study visit. If a woman is sexually active and has no history of hysterectomy or tubal ligation or menopause, she must agree to use a prescription birth control method or a barrier birth control method. * Negative beta-human chorionic gonadotropin (β-HCG) pregnancy test (urine or serum) on day of enrollment for any women unless she is post-menopause for 24 consecutive months or has undergone a surgical procedure that precludes pregnancy.
Exclusion criteria
* Previous receipt of humanized or human monoclonal antibody whether licensed or investigational. * Ongoing AIDS-related opportunistic infection (including oral thrush). * Active injection drug use within previous 12 months. * History of a severe allergic reaction with generalized urticaria, angioedema, or anaphylaxis in the 2 years prior to enrollment. * History of chronic urticaria requiring daily treatment. * Physical finding on examination considered indicative of significant disease such as murmur (other than functional), hepatosplenomegaly, or focal neurologic deficit. * Hypertension that is not well controlled by medication. * Hepatitis B surface antigen positive at any time in the past. * Hepatitis C antibody positive at any time in the past. * Untreated syphilis. * Estimated glomerular filtration rate (GFR) less than 50 ml/min within the past 90 days. * Pregnant or breastfeeding. * Receipt of licensed vaccine or other investigational study agent within 28 days prior to enrollment or past participation in an investigational HIV vaccine study with receipt of active product. * Current or planned participation in another interventional clinical trial during the study period. * Chronic or recurrent use of medications that modify host immune response, e.g., oral or parenteral steroids, cancer chemotherapy. * Any other chronic or clinically significant medical condition that in the opinion of investigator would jeopardize the safety or rights of the volunteer. 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, psychiatric disorders, heart disease, or cancer. * Study site employee.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Event | Measured up to 10 weeks after last infusion of VRC01 or placebo | Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo |
| Number of Participants With Sustained Virologic Suppression | Measured through 24 weeks after ATI | Number of participants who sustained virologic control (HIV RNA \<50 copies/mL), without indication for ART resumption at week 24. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to ART Resumption for Any Reason After Cessation of ART | Measured from Baseline ATI through ART resumption. | This is the days from ATI to ART resumptions. |
| Number of Participants With Detectable HIV-1 RNA Via Single Copy Assay | Measured from Baseline ATI through ART resumption. | This is number of participants who had detectable HIV-1 RNA via the ultrasensitive single copy assay prior to detectability on the routine assay. |
| Change in CD4+ T Cell Count From ATI to ART Resumption | Measured from Baseline ATI through ART resumption | This is change in CD4+ T cell count from ATI to ART resumption. |
| Total HIV DNA in the Peripheral Compartment | Measured from ATI through 6 months after ART resumption | This is total HIV DNA levels at baseline ATI, ART resumption and 6 month after ART resumption |
| Time to Viral Rebound After Cessation of ART | Measured from Baseline ATI through ART resumption. | This is the days from Analytic Treatment Interruption (ATI) to: 1. HIV RNA \>= 20 copies/mL. 2. HIV RNA \>= 1000 copies/mL |
| Number of Participants With Acute Retroviral Syndrome (ARS) | Measured from Baseline ATI through ART resumption. | This is the number of participants who have developed during ATI. |
| Neuropsychological Battery Performance | Measured from Baseline ATI through ART resumption. | This is a NPZ-4 score,a 4-test NP battery evaluated fine motor function/manual dexterity \[Grooved Pegboard test (GP), non-dominant hand\], psychomotor speed \[Color Trails 1 (CT1), Trail Making A (TM)\], and executive function/set shifting \[Color Trails 2 (CT2)\]. Individual test raw scores were converted to z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance and lower cognitive impairment. |
| Computed Score on the Control and Attention Task (i.e., Flanker Task) | Measured from Baseline ATI through ART resumption. | The Flanker is a measure of executive function, specifically tapping inhibitory control and attention.The scores range from 0 to 10. A higher scores indicate higher levels of ability to attend to relevant stimuli and inhibit attention from irrelevant stimuli. |
| Number of Participants Hospitalized. | Measured up to 10 weeks after the last infusion of VRC01 or placebo | Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo |
| Level of Rebound Viremia After Cessation of ART | Measured from Baseline ATI through ART resumption. | This is the HIV-1 RNA levels (copies/mL) at first detection and ART resumption. |
Countries
Thailand
Participant flow
Recruitment details
This study was conducted at the Thai Red Cross AIDS Research Centre in Bangkok, Thailand. Participants were recruited between 9 August 2016 and 9 January 2017, from ongoing Acute HIV Infection (AHI) cohorts and received ART during AHI via a separately-funded protocol (clinicaltrials.gov NCT00796263).
Pre-assignment details
Twenty-three participants were enrolled, 4 were withdrawn prior to randomization because of the unavailability of study product in-country, and 19 were randomized with 5 assigned to placebo and 14 to VRC01. One VRC01 recipient experienced severe generalized urticaria during the first study infusion and did not complete the study.
Participants by arm
| Arm | Count |
|---|---|
| VRC01 Participants will receive an intravenous (IV) infusion of 40 mg/kg of VRC01 at Week 0 and every 3 weeks until Week 24 or until criteria for resumption of ART are met.
VRC01: 40 mg/kg; administered IV | 13 |
| Placebo for VRC01 Participants will receive an IV infusion of placebo at Week 0 and every 3 weeks until Week 24 or until criteria for resumption of ART are met.
Placebo for VRC01: Sodium Chloride for Injection 0.9%, USP; administered IV | 5 |
| Total | 18 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 |
Baseline characteristics
| Characteristic | VRC01 | Placebo for VRC01 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 5 Participants | 18 Participants |
| Age, Continuous | 32 years | 25 years | 29 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 13 Participants | 5 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Feibig stage at ART initiation III (IgM+, WB-) | 5 Participants | 2 Participants | 7 Participants |
| Feibig stage at ART initiation II (p24+, IgM-) | 7 Participants | 3 Participants | 10 Participants |
| Feibig stage at ART initiation I (RNA+, p24-) | 1 Participants | 0 Participants | 1 Participants |
| HIV-subtype B | 3 Participants | 1 Participants | 4 Participants |
| HIV-subtype CRF01_AE | 8 Participants | 4 Participants | 12 Participants |
| HIV-subtype CRF01_AE and B co-infection | 1 Participants | 0 Participants | 1 Participants |
| HIV-subtype CRF01_AE/B/C recombinant | 1 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Thailand | 13 Participants | 5 Participants | 18 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 13 Participants | 5 Participants | 18 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 14 | 0 / 5 |
| other Total, other adverse events | 14 / 14 | 5 / 5 |
| serious Total, serious adverse events | 0 / 14 | 0 / 5 |
Outcome results
Primary
Number of Participants With Serious Adverse Event
Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo
Time frame: Measured up to 10 weeks after last infusion of VRC01 or placebo
Population: Participants who were randomized to receive VRC01 or placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VRC01 | Number of Participants With Serious Adverse Event | 0 Participants |
| Placebo for VRC01 | Number of Participants With Serious Adverse Event | 0 Participants |
Primary
Number of Participants With Sustained Virologic Suppression
Number of participants who sustained virologic control (HIV RNA \<50 copies/mL), without indication for ART resumption at week 24.
Time frame: Measured through 24 weeks after ATI
Population: This is the number of participants who received at least one full dose of VRC01 or placbo, underwent Analytic Treatment Interruption (ATI).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VRC01 | Number of Participants With Sustained Virologic Suppression | 1 Participants |
| Placebo for VRC01 | Number of Participants With Sustained Virologic Suppression | 0 Participants |
p-value: 1Fisher Exact
Secondary
Change in CD4+ T Cell Count From ATI to ART Resumption
This is change in CD4+ T cell count from ATI to ART resumption.
Time frame: Measured from Baseline ATI through ART resumption
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VRC01 | Change in CD4+ T Cell Count From ATI to ART Resumption | -37 cells/mm^3 |
| Placebo for VRC01 | Change in CD4+ T Cell Count From ATI to ART Resumption | -21 cells/mm^3 |
p-value: 0.693Wilcoxon (Mann-Whitney)
Secondary
Computed Score on the Control and Attention Task (i.e., Flanker Task)
The Flanker is a measure of executive function, specifically tapping inhibitory control and attention.The scores range from 0 to 10. A higher scores indicate higher levels of ability to attend to relevant stimuli and inhibit attention from irrelevant stimuli.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 | Computed Score on the Control and Attention Task (i.e., Flanker Task) | Baseline ATI | 8.24 score |
| VRC01 | Computed Score on the Control and Attention Task (i.e., Flanker Task) | ART resumption | 8.4 score |
| Placebo for VRC01 | Computed Score on the Control and Attention Task (i.e., Flanker Task) | Baseline ATI | 8.36 score |
| Placebo for VRC01 | Computed Score on the Control and Attention Task (i.e., Flanker Task) | ART resumption | 8.41 score |
Comparison: Comparison between groups at baseline ATI.p-value: 0.522Wilcoxon (Mann-Whitney)
Comparison: A comparison between groups at ART resumption.p-value: 0.961Wilcoxon (Mann-Whitney)
Comparison: A comparison between baseline ATI and ART resumption within VRC01 group.p-value: 0.002Wilcoxon signed-rank test
Comparison: A comparison between baseline ATI and ART resumption within Placebo group.p-value: 0.043Wilcoxon signed-rank test
Secondary
Level of Rebound Viremia After Cessation of ART
This is the HIV-1 RNA levels (copies/mL) at first detection and ART resumption.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 | Level of Rebound Viremia After Cessation of ART | HIV-1 RNA at first detection | 105 copies/mL |
| VRC01 | Level of Rebound Viremia After Cessation of ART | HIV-1 RNA at ART resumption | 3440 copies/mL |
| Placebo for VRC01 | Level of Rebound Viremia After Cessation of ART | HIV-1 RNA at first detection | 1015 copies/mL |
| Placebo for VRC01 | Level of Rebound Viremia After Cessation of ART | HIV-1 RNA at ART resumption | 3845 copies/mL |
p-value: 0.027Wilcoxon (Mann-Whitney)
p-value: 0.588Wilcoxon (Mann-Whitney)
Secondary
Neuropsychological Battery Performance
This is a NPZ-4 score,a 4-test NP battery evaluated fine motor function/manual dexterity \[Grooved Pegboard test (GP), non-dominant hand\], psychomotor speed \[Color Trails 1 (CT1), Trail Making A (TM)\], and executive function/set shifting \[Color Trails 2 (CT2)\]. Individual test raw scores were converted to z-scores. Z-scores range from -3 standard deviations up to +3 standard deviations. Higher scores indicate better test performance and lower cognitive impairment.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least one full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 | Neuropsychological Battery Performance | NPZ-4 at baseline ATI | 0.87 Z-score |
| VRC01 | Neuropsychological Battery Performance | NPZ- at ART resumption | 1.25 Z-score |
| Placebo for VRC01 | Neuropsychological Battery Performance | NPZ-4 at baseline ATI | 1.19 Z-score |
| Placebo for VRC01 | Neuropsychological Battery Performance | NPZ- at ART resumption | 1.04 Z-score |
Comparison: Comparison between arms at baseline ATIp-value: 0.961Wilcoxon (Mann-Whitney)
Comparison: Comparison between arms at ART resumptionp-value: 0.805Wilcoxon (Mann-Whitney)
Comparison: Comparison between Baseline and ART resumption within VRC01 arm.p-value: 0.221Wilcoxon signed-rank test
Comparison: Comparison between Baseline and ART resumption within Placebo arm.p-value: 0.5Wilcoxon signed-rank test
Secondary
Number of Participants Hospitalized.
Participants were monitored for up to 10 weeks after the last infusion of VRC01 or placebo
Time frame: Measured up to 10 weeks after the last infusion of VRC01 or placebo
Population: Participants who have been randomized to receive VRC01 or Placebo.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VRC01 | Number of Participants Hospitalized. | 0 Participants |
| Placebo for VRC01 | Number of Participants Hospitalized. | 0 Participants |
Secondary
Number of Participants With Acute Retroviral Syndrome (ARS)
This is the number of participants who have developed during ATI.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least one full dose of VRC01 or Placebo and underwent treatment interruption.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VRC01 | Number of Participants With Acute Retroviral Syndrome (ARS) | 0 Participants |
| Placebo for VRC01 | Number of Participants With Acute Retroviral Syndrome (ARS) | 0 Participants |
Secondary
Number of Participants With Detectable HIV-1 RNA Via Single Copy Assay
This is number of participants who had detectable HIV-1 RNA via the ultrasensitive single copy assay prior to detectability on the routine assay.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| VRC01 | Number of Participants With Detectable HIV-1 RNA Via Single Copy Assay | 8 Participants |
| Placebo for VRC01 | Number of Participants With Detectable HIV-1 RNA Via Single Copy Assay | 3 Participants |
Secondary
Time to ART Resumption for Any Reason After Cessation of ART
This is the days from ATI to ART resumptions.
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least one full dose of VRC01 or placebo and underwent ATI.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| VRC01 | Time to ART Resumption for Any Reason After Cessation of ART | 35 days |
| Placebo for VRC01 | Time to ART Resumption for Any Reason After Cessation of ART | 23 days |
p-value: 0.031Log Rank
Secondary
Time to Viral Rebound After Cessation of ART
This is the days from Analytic Treatment Interruption (ATI) to: 1. HIV RNA \>= 20 copies/mL. 2. HIV RNA \>= 1000 copies/mL
Time frame: Measured from Baseline ATI through ART resumption.
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 | Time to Viral Rebound After Cessation of ART | Time from ATI to HIV-1 RNA >= 20 copies/mL | 29 days |
| VRC01 | Time to Viral Rebound After Cessation of ART | Time from ATI to HIV-1 RNA >= 1000 copies/mL | 33 days |
| Placebo for VRC01 | Time to Viral Rebound After Cessation of ART | Time from ATI to HIV-1 RNA >= 20 copies/mL | 14 days |
| Placebo for VRC01 | Time to Viral Rebound After Cessation of ART | Time from ATI to HIV-1 RNA >= 1000 copies/mL | 14 days |
Comparison: A comparison of time from ATI to HIV-1 RNA \>= 20 copies/mL between arms.p-value: 0.051Log Rank
Comparison: A comparison of time from ATI to HIV-1 RNA \>= 1000 copies/mL between arms.p-value: 0.01Log Rank
Secondary
Total HIV DNA in the Peripheral Compartment
This is total HIV DNA levels at baseline ATI, ART resumption and 6 month after ART resumption
Time frame: Measured from ATI through 6 months after ART resumption
Population: Participants who received at least 1 full dose of VRC01 or Placebo and underwent ATI.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at baseline ATI | 16 copies/10^6 CD4 T cells |
| VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at ART resumption | 24 copies/10^6 CD4 T cells |
| VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at 6 months after ART resumption | 9 copies/10^6 CD4 T cells |
| Placebo for VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at baseline ATI | 3 copies/10^6 CD4 T cells |
| Placebo for VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at ART resumption | 39 copies/10^6 CD4 T cells |
| Placebo for VRC01 | Total HIV DNA in the Peripheral Compartment | Total HIV DNA at 6 months after ART resumption | 15 copies/10^6 CD4 T cells |
Comparison: A comparison of total HIV DNA at baseline ATI and ART resumption within the VRC01 arm.p-value: 0.15Wilcoxon signed-rank test
Comparison: A comparison of total HIV DNA at baseline ATI and ART resumption within the placebo arm.p-value: 0.04Wilcoxon signed-rank test
Comparison: A comparison of total HIV DNA at ART resumption and 6 months after ART resumption within the VRC01 arm.p-value: 0.002Wilcoxon signed-rank test
Comparison: A comparison of total HIV DNA at ART resumption and 6 months after ART resumption within the placebo arm.p-value: 0.22Wilcoxon signed-rank test
Comparison: A comparison of total HIV DNA atbaseline ATI and 6 months after ART resumption within the VRC01 arm.p-value: 0.05Wilcoxon signed-rank test
Comparison: A comparison of total HIV DNA at baeline ATI versus 6 months after ART resumption in the placebo armp-value: 0.22Wilcoxon signed-rank test