Dose-Response Study of Ibalizumab (Monoclonal Antibody) Plus Optimized Background Regimen in Patients With HIV-1 (TMB-202)

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)

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).

Study Overview

• Status: Completed
• Conditions: HIV
• Intervention / Treatment: Drug: Ibalizumab; Drug: Ibalizumab

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

• Study Type: Interventional
• Enrollment (Actual): 113
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00909
    • Clinical Research Puerto Rico
  • San Juan, Puerto Rico, 00909
    • Hope Clinical Research
• United States
  • California
    • Beverly Hills, California, United States, 90211
      • AIDS Health Care Foundation - Research
    • Long Beach, California, United States, 90813
      • Living Hope Clinical Foundation
    • Los Angeles, California, United States, 90027
      • Kaiser Permanente Medical Center
    • San Francisco, California, United States, 94115
      • Quest Clinical Research
    • San Francisco, California, United States, 94118
      • Kaiser Permanente Medical Center Research Unit
  • Colorado
    • Denver, Colorado, United States, 80206
      • National Jewish Medical & Research Center
    • Denver, Colorado, United States, 80205
      • Kaiser Permanente of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20009
      • Whitman-Walker Clinic
  • Florida
    • Atlantis, Florida, United States, 33462
      • South Florida Clinical Research
    • Miami, Florida, United States, 33136
      • University of Miami, Miller School of Medicine
    • Orlando, Florida, United States, 32802
      • Orlando Immunology Center
    • Port St. Lucie, Florida, United States, 34952
      • Associates in Infectious Diseases
    • Vero Beach, Florida, United States, 32960
      • Treasure Coast Infectious Disease Consultants
    • West Palm Beach, Florida, United States, 33401
      • Triple O Medical Services, Inc.
  • Illinois
    • Chicago, Illinois, United States, 60657
      • Northstar Medical Center
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine - Wishard Memorial Hospital
  • New Jersey
    • Newark, New Jersey, United States, 07102
      • St. Michael's Medical Center
  • New York
    • New York, New York, United States, 10018
      • AIDS Community Research Initiative of America
  • North Carolina
    • Greenville, North Carolina, United States, 27834
      • The Brody School of Medicine at ECU
  • Oregon
    • Portland, Oregon, United States, 97210
      • The Research & Educational Group
  • Texas
    • Austin, Texas, United States, 78705
      • Central Texas Clinical Research
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Disease Consultants
    • Harlingen, Texas, United States, 78550
      • Valley AIDS Council
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center
    • Houston, Texas, United States, 77004
      • Therapeutic Concepts
    • Houston, Texas, United States, 77098
      • Research Access Network
    • Houston, Texas, United States, 77036
      • Nationsmed Clinical Research
    • Houston, Texas, United States, 77098
      • Dr. Gordon E. Crofoot, MD, PA

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Ibalizumab 800 mg; every 2 weeks, combined with an Optimized Background Regimen	Drug: Ibalizumab; Ibalizumab 800 mg IV every 2 weeks; Other Names: TNX-355; Hu5A8; Drug: Ibalizumab; Ibalizumab 2000 mg IV every 4 weeks; Other Names: TNX-355; Hu5A8
ACTIVE_COMPARATOR: Ibalizumab 2000 mg; every 4 weeks, combined with an Optimized Background Regimen	Drug: Ibalizumab; Ibalizumab 800 mg IV every 2 weeks; Other Names: TNX-355; Hu5A8; Drug: Ibalizumab; Ibalizumab 2000 mg IV every 4 weeks; 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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Week 24
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.	Week 24
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.	Week 24
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.	Week 24

Collaborators and Investigators

• Sponsor: TaiMed Biologics Inc.
• Investigators: Study Director: Stanley T. Lewis, MD, TaiMed Biologics Inc.

Study record dates

Study Major Dates

• Study Start: August 1, 2008
• Primary Completion (ACTUAL): April 1, 2011
• Study Completion (ACTUAL): April 1, 2011

Study Registration Dates

• First Submitted: October 30, 2008
• First Submitted That Met QC Criteria: October 30, 2008
• First Posted (ESTIMATE): November 2, 2008

Study Record Updates

• Last Update Posted (ESTIMATE): May 5, 2014
• Last Update Submitted That Met QC Criteria: April 17, 2014
• Last Verified: April 1, 2014

More Information

Terms related to this study

• Keywords: HIV; antibody; resistant; infusion; resistance; CD4; monoclonal; ibalizumab; experienced; TNX355; TNX-355; TMB355; TMB-355
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Anti-HIV Agents; Anti-Retroviral Agents; Immunologic Factors; Antibodies, Monoclonal; Ibalizumab
• Other Study ID Numbers: TMB-202 Amendment 2