HIV
Conditions
Keywords
HIV, CD4, experienced, resistant, resistance, monoclonal, antibody, infusion, ibalizumab, TNX355, TNX-355, TMB355, TMB-355
Brief summary
The investigational product, ibalizumab, is a humanized IgG4 monoclonal antibody administered via intravenous infusion at 800 mg every 2 weeks or at 2000 mg every 4 weeks. In addition to study drug, all patients will receive an optimized background regimen (OBR), which is a standard-of-care regimen selected by the investigator prior to randomization that is comprised of 2-4 antiretroviral agents. These agents must have been approved by the local regulatory agency or be available through expanded-access programs for treatment of human immunodeficiency virus (HIV).
Detailed description
The primary objectives of this study are to: * Evaluate the dose-response relationship of antiviral activity of the ibalizumab dose regimens at Week 24 in order to determine the optimal dose and regimen. The primary evaluation of effectiveness will be based on the proportion of patients achieving undetectable viral loads at Week 24. * Evaluate the safety and tolerability of two dose regimens of ibalizumab for dose selection The secondary objectives of this study are to: * Evaluate changes from Baseline in viral load, CD4+ cell counts, and time to loss of virologic response (TLOVR) * Characterize HIV-1 sensitivity/susceptibility changes associated with ibalizumab administration in combination with OBR * Determine the presence and significance of anti-ibalizumab antibodies, if any (immunogenicity of ibalizumab) * Assess CD4 receptor density and occupancy * Determine the impact of ibalizumab on quality of life as assessed by patient-reported outcomes on questionnaires * Evaluate the pharmacokinetic profile of two dose regimens of ibalizumab at steady state
Interventions
DRUGIbalizumab
Ibalizumab 800 mg IV every 2 weeks
Sponsors
TaiMed Biologics Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Are capable of understanding and have voluntarily signed the informed consent document 2. Have documented HIV-1 infection by official, signed, written history (eg, laboratory report), otherwise an HIV-antibody test will be performed 3. Have no acquired immunodeficiency syndrome (AIDS)-defining events in the 3 months before screening, other than cutaneous Kaposi's sarcoma or wasting syndrome due to HIV 4. Are able and willing to comply with all protocol requirements and procedures 5. Are 18 years of age or older 6. Have a life expectancy that is \>6 months. 7. Have a viral load \>1,000 copies/mL and documented decreased susceptibility to at least one NRTI, one NNRTI, and one PI, as measured by resistance testing 8. Are receiving a stable highly active antiretroviral regimen for at least 8 weeks before screening and are willing to continue that regimen until the baseline visit, OR (in the past 8 weeks) have failed and are off therapy and are willing to stay off therapy until the baseline visit 9. Have viral sensitivity/susceptibility to at least one agent (OSS criteria) as determined by the screening resistance tests and be willing and able to be treated with at least one agent to which the patient's viral isolate is sensitive/susceptible according to the screening resistance tests as a component of OBR 10. If sexually active, are willing to use an effective method of contraception during the study and for 30 days after the last administration of the study drug
Exclusion criteria
1. Any active AIDS-defining illness per Category C conditions according to the Center for Disease Control (CDC) Classification System for HIV Infection, with the following exceptions: cutaneous Kaposi's sarcoma and wasting syndrome due to HIV 2. Any significant diseases (other than HIV-1 infection) or clinically significant findings, including psychiatric and behavioral problems, determined from screening, medical history and/or physical examination that, in the investigator's opinion, would preclude the patient from participating in this study 3. Any significant acute illness within 1 week before the initial administration of study drug 4. Any active infection secondary to HIV requiring acute therapy; however, patients that require maintenance therapy (ie, secondary prophylaxis for opportunistic infections) will be eligible for the study 5. Any immunomodulating therapy (including interferon), systemic steroids, or systemic chemotherapy within 12 weeks before randomization 6. Any investigational therapy within 30 days before randomization, except for HIV-agents available in expanded-access programs 7. Any prior exposure to ibalizumab (formerly TNX-355 and Hu5A8) 8. Any vaccination within 21 days before randomization 9. Any female patient who either is pregnant, intends to become pregnant, or is currently breast-feeding 10. Any current alcohol or illicit drug use that, in the investigator's opinion, will interfere with the patient's ability to comply with the study schedule and protocol evaluations 11. Any previous clinically significant allergy or hypersensitivity to any excipient in the ibalizumab formulation 12. Any radiation therapy during the 28 days before first administration of investigational medication 13. Any grade 3 or 4 toxicity according to the Division of AIDS grading scale, except for the following asymptomatic grade 3 events: triglyceride elevation & total cholesterol elevation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Proportion of Patients Achieving Undetectable Viral Loads at Week 24. | 24 weeks | For the primary efficacy analysis, undetectable was defined as having HIV-1 RNA below the limit of assay detection at \<50 copies/mL. The primary efficacy endpoint was analyzed using Fisher exact test. The primary analysis was performed using the ITT population and both the missing data equals treatment failure (MEF) and last observation carried forward (LOCF) methods. The more conservative MEF results are recorded here. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mean Change From Baseline in Viral Load (log10) at Week 24/EOS | Week 24 / End of Study | The mean change in HIV-1 RNA (log10) from the Baseline measurement was analyzed at Week 24/End of Study using a generalized linear model at each scheduled study visit. |
| Mean Change From Baseline in CD4+ T-Cell Count at Week 24/EOS | Week 24 / End of Study | The mean change in CD4+ T-cell count from the Baseline measurement at Week 24/End of Study was summarized at each scheduled time point by treatment group. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Patients With Viral Load <200 Copies/mL at Week 24 | Week 24 | This measure was assessed in the same manner as the primary efficacy analysis for the proportion of patients achieving HIV-1 RNA levels below 200 copies/mL at Week 24 of the study. |
| Proportion of Patients With a 0.5 log10 or Greater Reduction in Viral Load at Week 24 | Week 24 | This efficacy assessment was performed in the same manner as the primary efficacy analysis for the proportion of the total population achieving at least a 0.5 log10 reduction from the Baseline measurement in HIV-1 RNA at Week 24 of the study. |
| Proportion of Patients With Viral Load <400 Copies/mL at Week 24 | Week 24 | This efficacy measure was assessed in the same manner as the primary efficacy analysis to determine the proportion of the total population achieving HIV-1 RNA levels \<400 copies at Week 24 of the study. |
| Proportion of Patients With a 1.0 log10 or Greater Reduction in Viral Load at Week 24 | Week 24 | This efficacy assessment was performed in the same manner as the primary efficacy analysis for the proportion of the total population achieving at least a 1.0 log10 reduction from Baseline in HIV-1 RNA. |
Countries
Puerto Rico, United States
Participant flow
Recruitment details
Over the period from late 2008 through early 2010, a total of 113 patients were enrolled into the study from 35 study sites in the United States and Taiwan. The study sites were private medical practices, not-for-profit community clinics and university hospital clinics delivering HIV primary care.
Participants by arm
| Arm | Count |
|---|---|
| Ibalizumab 800 mg every 2 weeks, combined with an Optimized Background Regimen
Ibalizumab : Ibalizumab 800 mg IV every 2 weeks | 59 |
| Ibalizumab 2000 mg every 4 weeks, combined with an Optimized Background Regimen
Ibalizumab : Ibalizumab 2000 mg IV every 4 weeks | 54 |
| Total | 113 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 0 |
| Overall Study | Lost to Follow-up | 2 | 4 |
| Overall Study | Physician Decision | 2 | 1 |
| Overall Study | Protocol Violation | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 3 |
Baseline characteristics
| Characteristic | Ibalizumab 2000 mg | Total | Ibalizumab 800 mg |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 54 Participants | 112 Participants | 58 Participants |
| Age, Continuous | 47.9 years | 48.1 years | 48.3 years |
| CD4+ T-cell count | 112.4 cells/mL STANDARD_DEVIATION 118.5 | 109.3 cells/mL STANDARD_DEVIATION 104.7 | 106.4 cells/mL STANDARD_DEVIATION 91.3 |
| HIV-1 RNA (viral load) | 136,452.8 copies/mL | 125,082.2 copies/mL | 114,675.3 copies/mL |
| Number of active agents in OBR | 1.8 Pharmaceutical Agents STANDARD_DEVIATION 0.7 | 1.8 Pharmaceutical Agents STANDARD_DEVIATION 0.7 | 1.9 Pharmaceutical Agents STANDARD_DEVIATION 0.8 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 4 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 15 Participants | 27 Participants | 12 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 12 Participants | 4 Participants |
| Race (NIH/OMB) White | 28 Participants | 70 Participants | 42 Participants |
| Sex: Female, Male Female | 4 Participants | 12 Participants | 8 Participants |
| Sex: Female, Male Male | 50 Participants | 101 Participants | 51 Participants |
| Time from initial documented HIV infection | 16.9 years STANDARD_DEVIATION 6.2 | 17.0 years STANDARD_DEVIATION 5.4 | 17.0 years STANDARD_DEVIATION 4.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 46 / 59 | 44 / 54 |
| serious Total, serious adverse events | 7 / 59 | 3 / 54 |
Outcome results
Primary
The Proportion of Patients Achieving Undetectable Viral Loads at Week 24.
For the primary efficacy analysis, undetectable was defined as having HIV-1 RNA below the limit of assay detection at \<50 copies/mL. The primary efficacy endpoint was analyzed using Fisher exact test. The primary analysis was performed using the ITT population and both the missing data equals treatment failure (MEF) and last observation carried forward (LOCF) methods. The more conservative MEF results are recorded here.
Time frame: 24 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibalizumab 800 mg | The Proportion of Patients Achieving Undetectable Viral Loads at Week 24. | 44 percentage of participants |
| Ibalizumab 2000 mg | The Proportion of Patients Achieving Undetectable Viral Loads at Week 24. | 28 percentage of participants |
Secondary
Mean Change From Baseline in CD4+ T-Cell Count at Week 24/EOS
The mean change in CD4+ T-cell count from the Baseline measurement at Week 24/End of Study was summarized at each scheduled time point by treatment group.
Time frame: Week 24 / End of Study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibalizumab 800 mg | Mean Change From Baseline in CD4+ T-Cell Count at Week 24/EOS | 36.5 cell/mL | Standard Deviation 63 |
| Ibalizumab 2000 mg | Mean Change From Baseline in CD4+ T-Cell Count at Week 24/EOS | 39.8 cell/mL | Standard Deviation 80.1 |
Secondary
Mean Change From Baseline in Viral Load (log10) at Week 24/EOS
The mean change in HIV-1 RNA (log10) from the Baseline measurement was analyzed at Week 24/End of Study using a generalized linear model at each scheduled study visit.
Time frame: Week 24 / End of Study
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ibalizumab 800 mg | Mean Change From Baseline in Viral Load (log10) at Week 24/EOS | -1.6 log10 copies/mL | Standard Deviation 1.3 |
| Ibalizumab 2000 mg | Mean Change From Baseline in Viral Load (log10) at Week 24/EOS | -1.5 log10 copies/mL | Standard Deviation 1.4 |
Other Pre-specified
Proportion of Patients With a 0.5 log10 or Greater Reduction in Viral Load at Week 24
This efficacy assessment was performed in the same manner as the primary efficacy analysis for the proportion of the total population achieving at least a 0.5 log10 reduction from the Baseline measurement in HIV-1 RNA at Week 24 of the study.
Time frame: Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibalizumab 800 mg | Proportion of Patients With a 0.5 log10 or Greater Reduction in Viral Load at Week 24 | 68 percentage of patients |
| Ibalizumab 2000 mg | Proportion of Patients With a 0.5 log10 or Greater Reduction in Viral Load at Week 24 | 59 percentage of patients |
Other Pre-specified
Proportion of Patients With a 1.0 log10 or Greater Reduction in Viral Load at Week 24
This efficacy assessment was performed in the same manner as the primary efficacy analysis for the proportion of the total population achieving at least a 1.0 log10 reduction from Baseline in HIV-1 RNA.
Time frame: Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibalizumab 800 mg | Proportion of Patients With a 1.0 log10 or Greater Reduction in Viral Load at Week 24 | 63 percentage of patients |
| Ibalizumab 2000 mg | Proportion of Patients With a 1.0 log10 or Greater Reduction in Viral Load at Week 24 | 59 percentage of patients |
Other Pre-specified
Proportion of Patients With Viral Load <200 Copies/mL at Week 24
This measure was assessed in the same manner as the primary efficacy analysis for the proportion of patients achieving HIV-1 RNA levels below 200 copies/mL at Week 24 of the study.
Time frame: Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibalizumab 800 mg | Proportion of Patients With Viral Load <200 Copies/mL at Week 24 | 53 percentage of patients |
| Ibalizumab 2000 mg | Proportion of Patients With Viral Load <200 Copies/mL at Week 24 | 43 percentage of patients |
Other Pre-specified
Proportion of Patients With Viral Load <400 Copies/mL at Week 24
This efficacy measure was assessed in the same manner as the primary efficacy analysis to determine the proportion of the total population achieving HIV-1 RNA levels \<400 copies at Week 24 of the study.
Time frame: Week 24
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ibalizumab 800 mg | Proportion of Patients With Viral Load <400 Copies/mL at Week 24 | 58 percentage of patients |
| Ibalizumab 2000 mg | Proportion of Patients With Viral Load <400 Copies/mL at Week 24 | 46 percentage of patients |