Dose-Response Study of Ibalizumab (Monoclonal Antibody) Plus Optimized Background Regimen in Patients With HIV-1

Study Overview
=================
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

Official Title
-----------------
A Phase 2b, Randomized, Double-Blinded, 48-Week, Multicenter, Dose-Response Study of Ibalizumab Plus an Optimized Background Regimen in Treatment-Experienced Patients Infected With HIV-1(Amended to 24-Weeks)

Conditions
-----------------
HIV

Intervention / Treatment
-----------------
* Drug: Ibalizumab
* Drug: Ibalizumab


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Are capable of understanding and have voluntarily signed the informed consent document Have documented HIV-1 infection by official, signed, written history (eg, laboratory report), otherwise an HIV-antibody test will be performed 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 Are able and willing to comply with all protocol requirements and procedures Are 18 years of age or older Have a life expectancy that is >6 months. 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 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 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 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: 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 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 Any significant acute illness within 1 week before the initial administration of study drug 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 Any immunomodulating therapy (including interferon), systemic steroids, or systemic chemotherapy within 12 weeks before randomization Any investigational therapy within 30 days before randomization, except for HIV-agents available in expanded-access programs Any prior exposure to ibalizumab (formerly TNX-355 and Hu5A8) Any vaccination within 21 days before randomization Any female patient who either is pregnant, intends to become pregnant, or is currently breast-feeding 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 Any previous clinically significant allergy or hypersensitivity to any excipient in the ibalizumab formulation Any radiation therapy during the 28 days before first administration of investigational medication 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Ibalizumab 800 mg<br>every 2 weeks, combined with an Optimized Background Regimen | Drug: Ibalizumab<br>* Ibalizumab 800 mg IV every 2 weeks<br>* Other names: TNX-355; Hu5A8;|
| Active Comparator: Ibalizumab 2000 mg<br>every 4 weeks, combined with an Optimized Background Regimen | Drug: Ibalizumab<br>* Ibalizumab 2000 mg IV every 4 weeks<br>* Other names: TNX-355; Hu5A8;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Week 24 / End of Study | 
| 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. | Week 24 / End of Study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
HIV, CD4, experienced, resistant, resistance, monoclonal, antibody, infusion, ibalizumab, TNX355, TNX-355, TMB355, TMB-355